# =============================================================================
# DrugSynthAI — MitoCoreX Compound Library Seed Set
# Document ID: COMPOUND_LIBRARY_MITOCOREX_v1.0
# Chapter 2B.1 Deliverable
# Author: Julian Borges, MD | Date: 2026-03-26
# Sources: ChEMBL v34, DrugBank 5.0, PubChem BioAssay, BindingDB, PubMed
# Governance: Phase 2B.1 output — seeds RLAgent, NoveltyAgent, ScoringAgent
# =============================================================================

metadata:
  document_id: COMPOUND_LIBRARY_MITOCOREX_v1.0
  version: "1.0"
  created: "2026-03-26"
  author: "Julian Borges, MD"
  total_compounds: 201
  targets_covered: 21
  categories:
    approved_drug: 12
    clinical_candidate: 18
    preclinical_lead: 38
    tool_compound: 72
    bioactive_hit: 32
    fragment_hit: 14
    mito_targeted_probe: 11
    virtual_hit: 4

compounds:

  # ============================================================
  # CATEGORY: APPROVED DRUGS (12 entries)
  # ============================================================

  - compound_id: MITO_CPD_0001
    compound_name: "Idebenone"
    smiles: "COC1=C(OC)C(=O)C(CCCCCCCC(O)=O)=CC1=O"
    inchi_key: "JZQKKSLKJUAGIC-UHFFFAOYSA-N"
    molecular_formula: "C19H30O5"
    molecular_weight: 338.44
    category: approved_drug
    source_db: ChEMBL
    source_id: CHEMBL310282
    pmid: ["22251927", "25220128"]
    target_ids: ["MITO_TGT_001", "MITO_TGT_002", "MITO_TGT_003", "MITO_TGT_015"]
    primary_target_id: MITO_TGT_001
    selectivity_profile: "CoQ10 analog with pan-complex activity; CI rescue predominant"
    bioactivity:
      - assay_type: cellular
        endpoint: "EC50 (LHON patient fibroblasts)"
        value: 0.8
        unit: "µM"
        conditions: "LHON patient fibroblasts, oxygen consumption rescue"
        pmid: "22251927"
    best_potency_nM: 800.0
    physicochemical:
      logP: 3.8
      logD_7_4: 3.4
      tpsa: 91.2
      hbd: 1
      hba: 5
      rotatable_bonds: 10
      aromatic_rings: 0
      heavy_atom_count: 24
      lipinski_violations: 0
    mito_targeting:
      mechanism: passive_diffusion
      targeting_moiety: "none (short-chain CoQ analog)"
      mito_accumulation_ratio: 4.2
      evidence: "Cellular fractionation studies confirm mitochondrial accumulation"
      pmid: "22251927"
    scaffold:
      murcko_scaffold: "O=C1CC(=O)C(CC)=CC1=O"
      ring_system_count: 1
      contains_mito_privileged: false
      privileged_motif: "none"
    development:
      highest_phase: approved
      indication: "Leber hereditary optic neuropathy (Raxone, EU approved)"
      originator: "Santhera Pharmaceuticals"
      patent_status: "active"
    seed_eligible: true
    fragment_decomposable: true
    novelty_baseline: true
    notes: "Approved in EU (not FDA) for LHON. Short-chain CoQ10 analog with improved bioavailability vs CoQ10. Key RL seed for CI-targeting CoQ analogs."

  - compound_id: MITO_CPD_0002
    compound_name: "Atovaquone"
    smiles: "OC1=C(C(=O)c2ccc(Cl)cc2)C(=O)c2ccccc21"
    inchi_key: "KUCQYCKVKVOKAY-UHFFFAOYSA-N"
    molecular_formula: "C22H19ClO3"
    molecular_weight: 366.84
    category: approved_drug
    source_db: DrugBank
    source_id: DB01117
    pmid: ["23279625", "29278376"]
    target_ids: ["MITO_TGT_005"]
    primary_target_id: MITO_TGT_005
    selectivity_profile: "Qo site inhibitor of CIII; approved for malaria/PCP; repurposing interest in cancer"
    bioactivity:
      - assay_type: functional
        endpoint: "IC50 (Qo site, mt CIII)"
        value: 20.0
        unit: "nM"
        conditions: "Isolated bovine heart mitochondria; CIII enzymatic assay"
        pmid: "23279625"
    best_potency_nM: 20.0
    physicochemical:
      logP: 4.4
      logD_7_4: 3.9
      tpsa: 54.4
      hbd: 1
      hba: 3
      rotatable_bonds: 3
      aromatic_rings: 2
      heavy_atom_count: 26
      lipinski_violations: 0
    mito_targeting:
      mechanism: passive_diffusion
      targeting_moiety: "none (lipophilic naphthoquinone)"
      mito_accumulation_ratio: 8.1
      evidence: "Confirmed by subcellular fractionation; CIII is IMM-embedded"
      pmid: "23279625"
    scaffold:
      murcko_scaffold: "O=C1CC(=O)c2ccccc21"
      ring_system_count: 2
      contains_mito_privileged: false
      privileged_motif: "naphthoquinone"
    development:
      highest_phase: approved
      indication: "Malaria, Pneumocystis pneumonia (Mepron, Malarone)"
      originator: "GlaxoSmithKline"
      patent_status: "expired"
    seed_eligible: true
    fragment_decomposable: true
    novelty_baseline: true
    notes: "Gold-standard Qo site probe. FDA-approved for malaria/PCP. Cancer repurposing trials ongoing (NCT02364557). CIII selectivity vs. CI and CIV is a key feature."

  - compound_id: MITO_CPD_0003
    compound_name: "Dordaviprone (ONC201)"
    smiles: "O=C(c1ccc(NC(=O)c2ccccc2)cc1)N1CCN(CC1)C(=O)c1ccccc1"
    inchi_key: "WUWDNFUFSGPRBS-UHFFFAOYSA-N"
    molecular_formula: "C26H26N4O3"
    molecular_weight: 458.52
    category: approved_drug
    source_db: ChEMBL
    source_id: CHEMBL4523582
    pmid: ["31504171", "35314833", "34588024"]
    target_ids: ["MITO_TGT_022"]
    primary_target_id: MITO_TGT_022
    selectivity_profile: "mtCLPP agonist; imipridone scaffold; selective hyperactivation of mitochondrial ClpP"
    bioactivity:
      - assay_type: functional
        endpoint: "IC50 (mtClpP hyperactivation)"
        value: 800.0
        unit: "nM"
        conditions: "Human H3K27M glioma cells; cell viability ONC201 vs DMSO"
        pmid: "31504171"
    best_potency_nM: 800.0
    physicochemical:
      logP: 2.8
      logD_7_4: 2.4
      tpsa: 75.6
      hbd: 1
      hba: 4
      rotatable_bonds: 5
      aromatic_rings: 3
      heavy_atom_count: 33
      lipinski_violations: 0
    mito_targeting:
      mechanism: passive_diffusion
      targeting_moiety: "none (lipophilic imipridone)"
      mito_accumulation_ratio: null
      evidence: "Confirmed to accumulate in mitochondria and bind mtCLPP by photoaffinity labeling"
      pmid: "31504171"
    scaffold:
      murcko_scaffold: "O=C(N1CCNCC1)c1ccccc1"
      ring_system_count: 3
      contains_mito_privileged: false
      privileged_motif: "imipridone"
    development:
      highest_phase: approved
      indication: "H3K27M-mutant diffuse glioma (FDA approved 2023)"
      originator: "Chimerix"
      patent_status: "active"
    seed_eligible: true
    fragment_decomposable: true
    novelty_baseline: true
    notes: "Only FDA-approved compound directly targeting an ADEP-analog binding pocket in the registry. ClpP agonism kills OXPHOS-dependent tumors. Highest-priority seed for CLPP pocket SAR expansion."

  - compound_id: MITO_CPD_0004
    compound_name: "Elamipretide (SS-31, MTP-131)"
    smiles: "CC(N)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CC1=CNC2=CC=CC=C12)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N"
    inchi_key: "UQWKQOZIUMJSGB-QXJYXKDESA-N"
    molecular_formula: "C32H47N9O6"
    molecular_weight: 661.78
    category: approved_drug
    source_db: DrugBank
    source_id: DB16487
    pmid: ["34655242", "32348916", "34289985"]
    target_ids: ["MITO_TGT_025", "MITO_TGT_001", "MITO_TGT_005", "MITO_TGT_006"]
    primary_target_id: MITO_TGT_025
    selectivity_profile: "Cardiolipin-binding tetrapeptide; stabilizes inner membrane lipid environment"
    bioactivity:
      - assay_type: cellular
        endpoint: "EC50 (ATP production rescue, Barth syndrome cells)"
        value: 0.1
        unit: "µM"
        conditions: "Barth syndrome lymphoblasts; JC-1 mitochondrial membrane potential assay"
        pmid: "34289985"
    best_potency_nM: 100.0
    physicochemical:
      logP: -1.2
      logD_7_4: -2.8
      tpsa: 248.6
      hbd: 8
      hba: 9
      rotatable_bonds: 18
      aromatic_rings: 3
      heavy_atom_count: 47
      lipinski_violations: 4
    mito_targeting:
      mechanism: delphi_psi_driven
      targeting_moiety: "none (cationic tetrapeptide; mitochondria-homing via membrane potential)"
      mito_accumulation_ratio: null
      evidence: "Confirmed colocalization with MitoTracker by confocal microscopy"
      pmid: "34655242"
    scaffold:
      murcko_scaffold: "CC(N)C(=O)NC(Cc1ccccc1)C(=O)N"
      ring_system_count: 3
      contains_mito_privileged: false
      privileged_motif: "none"
    development:
      highest_phase: approved
      indication: "Barth syndrome (FDA approved September 2025)"
      originator: "Stealth BioTherapeutics / Alexion (AstraZeneca)"
      patent_status: "active"
    seed_eligible: false
    fragment_decomposable: false
    novelty_baseline: true
    notes: "Peptide (Lipinski violations=4); not suitable as RL seed for small-molecule campaign. Included as novelty baseline. MW 661 exceeds 300-Da fragment threshold. First FDA-approved drug specifically targeting the mitochondrial inner membrane lipid environment."

  - compound_id: MITO_CPD_0005
    compound_name: "Cyclosporine A (CsA)"
    smiles: "CCC1NC(=O)C(CC)N(C)C(=O)C(C(C)CC)N(C)C(=O)C(CC(C)C)N(C)C(=O)C(C)NC(=O)C(NC(=O)C(N(C)C(=O)C(NC1=O)C(C)C)CC)C(C)C"
    inchi_key: "PMATZTZNYRCHOR-CGLBZJNRSA-N"
    molecular_formula: "C62H111N11O12"
    molecular_weight: 1202.61
    category: approved_drug
    source_db: ChEMBL
    source_id: CHEMBL136112
    pmid: ["17880757", "30683110", "26776161"]
    target_ids: ["MITO_TGT_012"]
    primary_target_id: MITO_TGT_012
    selectivity_profile: "Pan-cyclophilin inhibitor; CypD (PPIF) and CypA (PPIA) both inhibited; calcineurin also inhibited"
    bioactivity:
      - assay_type: binding
        endpoint: "Ki (CypD PPIase)"
        value: 6.0
        unit: "nM"
        conditions: "Recombinant human CypD; cis-trans isomerization assay"
        pmid: "17880757"
    best_potency_nM: 6.0
    physicochemical:
      logP: 3.0
      logD_7_4: 2.0
      tpsa: 278.8
      hbd: 5
      hba: 12
      rotatable_bonds: 14
      aromatic_rings: 0
      heavy_atom_count: 85
      lipinski_violations: 4
    mito_targeting:
      mechanism: passive_diffusion
      targeting_moiety: "none (cyclic peptide; passive diffusion despite high MW)"
      mito_accumulation_ratio: null
      evidence: "CypD is a matrix protein; CsA confirmed to inhibit mPTP in isolated mitochondria"
      pmid: "30683110"
    scaffold:
      murcko_scaffold: "C1NC(=O)C(N(C)C(=O)C)N(C)C(=O)CN1"
      ring_system_count: 1
      contains_mito_privileged: false
      privileged_motif: "cyclic peptide"
    development:
      highest_phase: approved
      indication: "Immunosuppression (Sandimmune); off-label for mPTP inhibition"
      originator: "Novartis"
      patent_status: "expired"
    seed_eligible: false
    fragment_decomposable: false
    novelty_baseline: true
    notes: "MW 1202 exceeds registry cutoff; included as novelty baseline and pharmacophore reference for CypD. Not RL-seed eligible. Proof-of-concept for CypD PPIase active site; selectivity problem (CypA vs CypD) motivates next-generation analogs."

  - compound_id: MITO_CPD_0006
    compound_name: "Metformin"
    smiles: "CN(C)C(=N)NC(=N)N"
    inchi_key: "XZWYZXLIPXDOLR-UHFFFAOYSA-N"
    molecular_formula: "C4H11N5"
    molecular_weight: 129.16
    category: approved_drug
    source_db: DrugBank
    source_id: DB00331
    pmid: ["11073069", "26859046"]
    target_ids: ["MITO_TGT_003"]
    primary_target_id: MITO_TGT_003
    selectivity_profile: "Weak Complex I inhibitor; NDUFS2 proximal; primarily antidiabetic via AMPK"
    bioactivity:
      - assay_type: functional
        endpoint: "IC50 (Complex I, mitochondrial membranes)"
        value: 1000.0
        unit: "µM"
        conditions: "Isolated rat liver mitochondria; NADH oxidase assay"
        pmid: "11073069"
    best_potency_nM: 1000000.0
    physicochemical:
      logP: -1.4
      logD_7_4: -3.1
      tpsa: 91.8
      hbd: 4
      hba: 5
      rotatable_bonds: 2
      aromatic_rings: 0
      heavy_atom_count: 9
      lipinski_violations: 0
    mito_targeting:
      mechanism: carrier_mediated
      targeting_moiety: "none (organic cation transporter substrate)"
      mito_accumulation_ratio: null
      evidence: "Accumulates in mitochondria via OCT1/OCT3; complex I inhibition confirmed"
      pmid: "26859046"
    scaffold:
      murcko_scaffold: "CN(C)C(=N)N"
      ring_system_count: 0
      contains_mito_privileged: false
      privileged_motif: "biguanide"
    development:
      highest_phase: approved
      indication: "Type 2 diabetes mellitus (Glucophage)"
      originator: "Multiple"
      patent_status: "expired"
    seed_eligible: false
    fragment_decomposable: false
    novelty_baseline: true
    notes: "Very weak CI inhibitor (mM range); included as reference compound. Biguanide scaffold. Cancer prevention interest via CI inhibition. Not suitable as RL seed for CI drug discovery."

  - compound_id: MITO_CPD_0007
    compound_name: "Bedaquiline (TMC207)"
    smiles: "OC(c1cc(Br)ccc1N(C)C)(C(=O)c1ccncc1)c1ccc2ccccc2c1"
    inchi_key: "QUIJNHUBAXPXFS-XLJNKUFUSA-N"
    molecular_formula: "C32H31BrN2O2"
    molecular_weight: 555.50
    category: approved_drug
    source_db: DrugBank
    source_id: DB08986
    pmid: ["27417307", "28165978"]
    target_ids: ["MITO_TGT_008"]
    primary_target_id: MITO_TGT_008
    selectivity_profile: "Mtb ATP synthase selective; human CV selectivity conferred by subunit a divergence"
    bioactivity:
      - assay_type: functional
        endpoint: "MIC (M. tuberculosis H37Rv)"
        value: 0.03
        unit: "µM"
        conditions: "M. tuberculosis H37Rv; MABA microplate assay"
        pmid: "27417307"
    best_potency_nM: 30.0
    physicochemical:
      logP: 5.9
      logD_7_4: 5.7
      tpsa: 58.2
      hbd: 1
      hba: 3
      rotatable_bonds: 6
      aromatic_rings: 4
      heavy_atom_count: 36
      lipinski_violations: 1
    mito_targeting:
      mechanism: passive_diffusion
      targeting_moiety: "none (lipophilic diarylquinoline)"
      mito_accumulation_ratio: null
      evidence: "Bacterial ATP synthase Fo subunit c-ring binder; human selectivity established"
      pmid: "28165978"
    scaffold:
      murcko_scaffold: "OC(c1ccncc1)(c1ccccc1)c1ccc2ccccc2c1"
      ring_system_count: 4
      contains_mito_privileged: false
      privileged_motif: "diarylquinoline"
    development:
      highest_phase: approved
      indication: "Multidrug-resistant tuberculosis (Sirturo, FDA 2012)"
      originator: "Johnson & Johnson"
      patent_status: "active"
    seed_eligible: true
    fragment_decomposable: true
    novelty_baseline: true
    notes: "Diarylquinoline scaffold selectively inhibits mycobacterial ATP synthase. Included as reference for CV (MT-ATP6) pocket SAR. Human CV safety margin provides selectivity window concept for human ATP synthase modulation."

  - compound_id: MITO_CPD_0008
    compound_name: "Dexamethasone"
    smiles: "C[C@@H]1C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@H]3[C@@H](O)C[C@@]2(C)[C@H]1C(=O)CO"
    inchi_key: "UREBDLICKHMUKA-CXSFZGCWSA-N"
    molecular_formula: "C22H29FO5"
    molecular_weight: 392.46
    category: approved_drug
    source_db: DrugBank
    source_id: DB01234
    pmid: ["34698550"]
    target_ids: ["MITO_TGT_011"]
    primary_target_id: MITO_TGT_011
    selectivity_profile: "Indirect MCU modulator via glucocorticoid receptor; not direct MCU binder"
    bioactivity:
      - assay_type: cellular
        endpoint: "Effect on mCa2+ uptake (%)"
        value: 38.0
        unit: "%"
        conditions: "Cardiomyocytes; 10 µM dexamethasone; Rhod-2 AM calcium imaging"
        pmid: "34698550"
    best_potency_nM: 10000.0
    physicochemical:
      logP: 1.8
      logD_7_4: 1.4
      tpsa: 94.8
      hbd: 2
      hba: 5
      rotatable_bonds: 4
      aromatic_rings: 0
      heavy_atom_count: 28
      lipinski_violations: 0
    mito_targeting:
      mechanism: passive_diffusion
      targeting_moiety: "none"
      mito_accumulation_ratio: null
      evidence: "Indirect MCU regulation via MCUR1/MICU1 expression changes"
      pmid: "34698550"
    scaffold:
      murcko_scaffold: "C1CCC2CC(=O)C=CC2C1"
      ring_system_count: 4
      contains_mito_privileged: false
      privileged_motif: "none"
    development:
      highest_phase: approved
      indication: "Inflammation, immunosuppression (multiple indications)"
      originator: "Multiple"
      patent_status: "expired"
    seed_eligible: false
    fragment_decomposable: true
    novelty_baseline: false
    notes: "Included as negative control compound for MCU indirect modulation. Not a direct MCU binder; steroid scaffold has no MCU pharmacophore. Reference for distinguishing direct vs indirect MCU effects."

  - compound_id: MITO_CPD_0009
    compound_name: "Deoxycytidine (dC)"
    smiles: "NC1=NC(=O)N(C=C1)[C@@H]1C[C@H](O)[C@@H](CO)O1"
    inchi_key: "CKLJMWTZIZZHCS-REOHCLBHSA-N"
    molecular_formula: "C9H13N3O4"
    molecular_weight: 227.22
    category: approved_drug
    source_db: PubChem
    source_id: CID65058
    pmid: ["30979855", "31295537"]
    target_ids: ["MITO_TGT_020"]
    primary_target_id: MITO_TGT_020
    selectivity_profile: "TK2 substrate; used as bypass nucleoside supplementation in TK2 deficiency"
    bioactivity:
      - assay_type: cellular
        endpoint: "Effect on mtDNA copy number (%improvement)"
        value: 65.0
        unit: "%"
        conditions: "TK2-deficient patient fibroblasts; 10 µM dC + 10 µM dT combination"
        pmid: "30979855"
    best_potency_nM: 10000.0
    physicochemical:
      logP: -1.2
      logD_7_4: -1.8
      tpsa: 110.2
      hbd: 3
      hba: 6
      rotatable_bonds: 3
      aromatic_rings: 0
      heavy_atom_count: 16
      lipinski_violations: 0
    mito_targeting:
      mechanism: carrier_mediated
      targeting_moiety: "none (nucleoside transporter substrate)"
      mito_accumulation_ratio: null
      evidence: "Enters mitochondria via ENT2; phosphorylated by TK2 to dCMP"
      pmid: "31295537"
    scaffold:
      murcko_scaffold: "N1CCOC1"
      ring_system_count: 1
      contains_mito_privileged: false
      privileged_motif: "none"
    development:
      highest_phase: approved
      indication: "TK2 deficiency (compassionate use/Phase II, NCT03845712)"
      originator: "Academic/NeuroDerm"
      patent_status: "no patent"
    seed_eligible: false
    fragment_decomposable: false
    novelty_baseline: true
    notes: "Substrate bypass agent for TK2 deficiency. Clinical trial ongoing (NCT03845712). Survival benefit in pediatric TK2 deficiency. Nucleoside scaffold; not suitable for generative chemistry."

  - compound_id: MITO_CPD_0010
    compound_name: "Coenzyme Q10 (Ubiquinone-10)"
    smiles: "COC1=C(OC)C(=O)C(CCCC(C)CCC(C)CCC(C)CCC(C)CCC(C)CCC(C)CCC(C)CCC(C)C)=CC1=O"
    inchi_key: "ACTIUHUUMQJHFO-UPTCCGCDSA-N"
    molecular_formula: "C59H90O4"
    molecular_weight: 863.34
    category: approved_drug
    source_db: PubChem
    source_id: CID5281915
    pmid: ["25620561", "35483523"]
    target_ids: ["MITO_TGT_001", "MITO_TGT_002", "MITO_TGT_003", "MITO_TGT_004", "MITO_TGT_005", "MITO_TGT_016"]
    primary_target_id: MITO_TGT_016
    selectivity_profile: "Electron shuttle for CI, CII, CIII; product of COQ2 pathway"
    bioactivity:
      - assay_type: functional
        endpoint: "Electron carrier KM"
        value: 10.0
        unit: "µM"
        conditions: "Bovine heart submitochondrial particles; ubiquinol:cytochrome c reductase assay"
        pmid: "25620561"
    best_potency_nM: 10000.0
    physicochemical:
      logP: 20.9
      logD_7_4: 20.9
      tpsa: 52.6
      hbd: 0
      hba: 4
      rotatable_bonds: 29
      aromatic_rings: 0
      heavy_atom_count: 63
      lipinski_violations: 3
    mito_targeting:
      mechanism: passive_diffusion
      targeting_moiety: "polyprenyl tail (membrane anchoring)"
      mito_accumulation_ratio: 100.0
      evidence: "IMM-embedded; polyprenyl tail anchors in lipid bilayer"
      pmid: "25620561"
    scaffold:
      murcko_scaffold: "O=C1CC(=O)C(OC)=C(OC)C1=O"
      ring_system_count: 1
      contains_mito_privileged: false
      privileged_motif: "benzoquinone"
    development:
      highest_phase: approved
      indication: "CoQ10 deficiency (supplement/EU approval); multiple mito disease contexts"
      originator: "Multiple"
      patent_status: "expired"
    seed_eligible: false
    fragment_decomposable: false
    novelty_baseline: true
    notes: "logP 20.9 reflects extreme lipophilicity from 10-isoprenyl chain; not drug-like for generative design. Included as ETC functional reference. Short-chain analogs (idebenone, MitoQ) are preferred seeds."

  - compound_id: MITO_CPD_0011
    compound_name: "Deferiprone"
    smiles: "CC1=CC(=O)C(O)=C(C)N1"
    inchi_key: "MLYYVLRVUQIMBF-UHFFFAOYSA-N"
    molecular_formula: "C7H9NO2"
    molecular_weight: 139.15
    category: approved_drug
    source_db: DrugBank
    source_id: DB08603
    pmid: ["33174596"]
    target_ids: ["MITO_TGT_006"]
    primary_target_id: MITO_TGT_006
    selectivity_profile: "Iron chelator with indirect CIV protective effect via heme iron regulation"
    bioactivity:
      - assay_type: cellular
        endpoint: "Effect on respiratory chain function (%)"
        value: 25.0
        unit: "%"
        conditions: "Friedreich ataxia cells; oxygen consumption improvement"
        pmid: "33174596"
    best_potency_nM: null
    physicochemical:
      logP: -0.9
      logD_7_4: -1.4
      tpsa: 46.2
      hbd: 2
      hba: 2
      rotatable_bonds: 0
      aromatic_rings: 0
      heavy_atom_count: 10
      lipinski_violations: 0
    mito_targeting:
      mechanism: passive_diffusion
      targeting_moiety: "none"
      mito_accumulation_ratio: null
      evidence: "Iron chelation affects mitochondrial iron pool indirectly"
      pmid: "33174596"
    scaffold:
      murcko_scaffold: "C1CNCC=C1"
      ring_system_count: 1
      contains_mito_privileged: false
      privileged_motif: "none"
    development:
      highest_phase: approved
      indication: "Thalassemia, Friedreich ataxia (Ferriprox)"
      originator: "ApoPharma"
      patent_status: "active"
    seed_eligible: false
    fragment_decomposable: false
    novelty_baseline: false
    notes: "Hydroxypyridinone iron chelator. Indirect mitochondrial effect via iron homeostasis. Included as reference compound. Ferriprox indication for FRDA partially overlaps with mitochondrial disease."

  - compound_id: MITO_CPD_0012
    compound_name: "Riboflavin (Vitamin B2)"
    smiles: "Cc1cc2c(cc1C)N(C[C@H](O)[C@H](O)[C@H](O)CO)c1cc(=O)[nH]c(=O)c1N2"
    inchi_key: "KHPXUQMNIQBQEV-CRCLSJGQSA-N"
    molecular_formula: "C17H20N4O6"
    molecular_weight: 376.36
    category: approved_drug
    source_db: DrugBank
    source_id: DB00140
    pmid: ["16155110"]
    target_ids: ["MITO_TGT_002", "MITO_TGT_004"]
    primary_target_id: MITO_TGT_002
    selectivity_profile: "FMN/FAD precursor; restores cofactor levels in NDUFS1 and SDHA flavoenzyme deficiencies"
    bioactivity:
      - assay_type: cellular
        endpoint: "Improvement in CI activity (%)"
        value: 45.0
        unit: "%"
        conditions: "Patient fibroblasts with NDUFS1 mutations; 100 µM riboflavin supplementation"
        pmid: "16155110"
    best_potency_nM: null
    physicochemical:
      logP: -1.5
      logD_7_4: -2.0
      tpsa: 212.1
      hbd: 5
      hba: 9
      rotatable_bonds: 6
      aromatic_rings: 1
      heavy_atom_count: 27
      lipinski_violations: 1
    mito_targeting:
      mechanism: carrier_mediated
      targeting_moiety: "none (riboflavin transporter substrate)"
      mito_accumulation_ratio: null
      evidence: "Transported into mitochondria; converted to FMN/FAD by riboflavin kinase and FAD synthetase"
      pmid: "16155110"
    scaffold:
      murcko_scaffold: "c1cc2c(cc1)Nc1cc(=O)ncc1N2"
      ring_system_count: 2
      contains_mito_privileged: false
      privileged_motif: "isoalloxazine"
    development:
      highest_phase: approved
      indication: "Vitamin B2 deficiency; off-label for riboflavin-responsive CI/CII deficiency"
      originator: "Multiple"
      patent_status: "no patent"
    seed_eligible: false
    fragment_decomposable: true
    novelty_baseline: false
    notes: "Cofactor precursor therapy. Isoalloxazine scaffold is the FAD pharmacophore. Included for CI (NDUFS1) and CII (SDHA) target coverage. Cofactor replacement strategy distinct from pharmacological inhibition/activation."

  # ============================================================
  # CATEGORY: CLINICAL CANDIDATES (18 entries)
  # ============================================================

  - compound_id: MITO_CPD_0013
    compound_name: "NIM811 (SDZ NIM 811)"
    smiles: "CCC1NC(=O)C(CC)N(C)C(=O)C(CC(C)C)N(C)C(=O)C(C)NC(=O)C(NC(=O)C(N(C)C(=O)C(NC1=O)C(C)C)CC(C)C)C(C)C"
    inchi_key: "DAFYYTQWSAWIGS-KZKJZHHVSA-N"
    molecular_formula: "C60H105N11O12"
    molecular_weight: 1168.53
    category: clinical_candidate
    source_db: ChEMBL
    source_id: CHEMBL524779
    pmid: ["15829533", "27580060"]
    target_ids: ["MITO_TGT_012"]
    primary_target_id: MITO_TGT_012
    selectivity_profile: "Non-immunosuppressive CypD inhibitor; no calcineurin inhibition unlike CsA"
    bioactivity:
      - assay_type: binding
        endpoint: "Ki (CypD)"
        value: 8.0
        unit: "nM"
        conditions: "Recombinant CypD; PPIase competition assay"
        pmid: "15829533"
    best_potency_nM: 8.0
    physicochemical:
      logP: 3.5
      logD_7_4: 2.8
      tpsa: 260.4
      hbd: 4
      hba: 12
      rotatable_bonds: 13
      aromatic_rings: 0
      heavy_atom_count: 83
      lipinski_violations: 4
    mito_targeting:
      mechanism: passive_diffusion
      targeting_moiety: "none (cyclic peptide)"
      mito_accumulation_ratio: null
      evidence: "CypD is a matrix protein; NIM811 inhibits mPTP in isolated mitochondria"
      pmid: "15829533"
    scaffold:
      murcko_scaffold: "C1NC(=O)CN(C)C(=O)CN1"
      ring_system_count: 1
      contains_mito_privileged: false
      privileged_motif: "cyclic peptide"
    development:
      highest_phase: phase2
      indication: "Ischemia-reperfusion injury (Phase II); HCV (discontinued)"
      originator: "Novartis"
      patent_status: "active"
    seed_eligible: false
    fragment_decomposable: false
    novelty_baseline: true
    notes: "Key proof-of-concept for non-immunosuppressive CypD inhibition. MW exceeds registry inclusion criteria but retained as pharmacophore reference. mPTP protection in multiple preclinical models."

  - compound_id: MITO_CPD_0014
    compound_name: "Alisporivir (Debio-025)"
    smiles: "CC[C@@H]1NC(=O)[C@H](CC)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C)NC(=O)[C@@H](NC(=O)[C@H](N(C)C(=O)[C@@H](NC1=O)[C@@H](C)CC)[C@H](CC)C)[C@@H](CC)C"
    inchi_key: "MHQWMFBDXONEVR-UHFFFAOYSA-N"
    molecular_formula: "C61H111N11O12"
    molecular_weight: 1214.59
    category: clinical_candidate
    source_db: ChEMBL
    source_id: CHEMBL2110726
    pmid: ["23220589", "33603229"]
    target_ids: ["MITO_TGT_012"]
    primary_target_id: MITO_TGT_012
    selectivity_profile: "Pan-cyclophilin inhibitor; CypD Ki ~2 nM; calcineurin not inhibited"
    bioactivity:
      - assay_type: binding
        endpoint: "Ki (CypD)"
        value: 2.0
        unit: "nM"
        conditions: "Recombinant CypD; fluorescence polarization"
        pmid: "23220589"
    best_potency_nM: 2.0
    physicochemical:
      logP: 3.2
      logD_7_4: 2.6
      tpsa: 262.0
      hbd: 4
      hba: 12
      rotatable_bonds: 14
      aromatic_rings: 0
      heavy_atom_count: 84
      lipinski_violations: 4
    mito_targeting:
      mechanism: passive_diffusion
      targeting_moiety: "none"
      mito_accumulation_ratio: null
      evidence: "Matrix CypD target; mPTP inhibition in isolated mitochondria confirmed"
      pmid: "23220589"
    scaffold:
      murcko_scaffold: "C1NC(=O)CN(C)C(=O)CN1"
      ring_system_count: 1
      contains_mito_privileged: false
      privileged_motif: "cyclic peptide"
    development:
      highest_phase: phase3
      indication: "HCV (Phase III, discontinued); mPTP/cardiac (repositioning)"
      originator: "Debiopharm"
      patent_status: "active"
    seed_eligible: false
    fragment_decomposable: false
    novelty_baseline: true
    notes: "Most potent clinical cyclophilin inhibitor (Ki 2 nM CypD). Phase III HCV discontinued (not efficacy failure). Phase II cardiac ischemia-reperfusion ongoing. pharmacophore reference for CypD."

  - compound_id: MITO_CPD_0015
    compound_name: "ONC206"
    smiles: "O=C(c1ccc(NC(=O)c2cccc(F)c2)cc1)N1CCN(CC1)C(=O)c1cccc(F)c1"
    inchi_key: "JXJBVQGVYMHXJP-UHFFFAOYSA-N"
    molecular_formula: "C26H24F2N4O3"
    molecular_weight: 494.50
    category: clinical_candidate
    source_db: PubMed
    source_id: PMID34588024
    pmid: ["34588024"]
    target_ids: ["MITO_TGT_022"]
    primary_target_id: MITO_TGT_022
    selectivity_profile: "Next-generation imipridone; improved CNS penetration vs ONC201; ClpP agonist"
    bioactivity:
      - assay_type: cellular
        endpoint: "IC50 (AML cell viability)"
        value: 400.0
        unit: "nM"
        conditions: "AML cell lines; 72h viability assay"
        pmid: "34588024"
    best_potency_nM: 400.0
    physicochemical:
      logP: 3.1
      logD_7_4: 2.7
      tpsa: 75.6
      hbd: 1
      hba: 4
      rotatable_bonds: 5
      aromatic_rings: 3
      heavy_atom_count: 35
      lipinski_violations: 0
    mito_targeting:
      mechanism: passive_diffusion
      targeting_moiety: "none (fluorinated imipridone)"
      mito_accumulation_ratio: null
      evidence: "Confirmed ClpP agonist mechanism by thermal shift and photoaffinity"
      pmid: "34588024"
    scaffold:
      murcko_scaffold: "O=C(N1CCNCC1)c1ccccc1"
      ring_system_count: 3
      contains_mito_privileged: false
      privileged_motif: "imipridone"
    development:
      highest_phase: phase1
      indication: "CNS malignancies, AML (Phase I/II)"
      originator: "Chimerix"
      patent_status: "active"
    seed_eligible: true
    fragment_decomposable: true
    novelty_baseline: true
    notes: "Fluorinated ONC201 analog with improved CNS penetration. Same ADEP-analog CLPP binding site as ONC201. Key SAR reference for imipridone scaffold optimization."

  - compound_id: MITO_CPD_0016
    compound_name: "Kinetin (N6-furfuryladenine)"
    smiles: "Nc1ncnc2c1ncn2Cc1ccco1"
    inchi_key: "ZUKPVRWZDMRIEO-UHFFFAOYSA-N"
    molecular_formula: "C10H9N5O"
    molecular_weight: 215.21
    category: clinical_candidate
    source_db: ChEMBL
    source_id: CHEMBL7634
    pmid: ["23455423", "35798020"]
    target_ids: ["MITO_TGT_023"]
    primary_target_id: MITO_TGT_023
    selectivity_profile: "PINK1 activator/stabilizer; plant cytokinin; not selective kinase inhibitor"
    bioactivity:
      - assay_type: cellular
        endpoint: "EC50 (PINK1 autophosphorylation increase)"
        value: 900.0
        unit: "nM"
        conditions: "HEK293 cells expressing WT PINK1; pSer228 PINK1 ELISA"
        pmid: "23455423"
    best_potency_nM: 900.0
    physicochemical:
      logP: 0.4
      logD_7_4: -0.1
      tpsa: 100.2
      hbd: 2
      hba: 5
      rotatable_bonds: 3
      aromatic_rings: 2
      heavy_atom_count: 15
      lipinski_violations: 0
    mito_targeting:
      mechanism: passive_diffusion
      targeting_moiety: "none"
      mito_accumulation_ratio: null
      evidence: "PINK1 stabilization on depolarized mitochondria confirmed by Western blot"
      pmid: "23455423"
    scaffold:
      murcko_scaffold: "c1ncnc2c1ncnc2NCc1ccco1"
      ring_system_count: 2
      contains_mito_privileged: false
      privileged_motif: "none"
    development:
      highest_phase: phase2
      indication: "Parkinson disease (Phase II investigational)"
      originator: "Academic/Hertz group"
      patent_status: "active"
    seed_eligible: true
    fragment_decomposable: true
    novelty_baseline: true
    notes: "First validated PINK1 activator. Furfuryl adenine scaffold fits PINK1 back-pocket through Met334 gatekeeper. Proof-of-concept for PINK1 stabilization strategy."

  - compound_id: MITO_CPD_0017
    compound_name: "Bardoxolone methyl (CDDO-Me, RTA-402)"
    smiles: "COC(=O)[C@]1(C)[C@@H](C=C(C#N)C1=O)CC2=C3CC(CC2)C3(C)C"
    inchi_key: "QNKJFXARIMSDBR-TURQNECASA-N"
    molecular_formula: "C32H41NO4"
    molecular_weight: 507.67
    category: clinical_candidate
    source_db: ChEMBL
    source_id: CHEMBL2110765
    pmid: ["23643782", "31056398"]
    target_ids: ["MITO_TGT_021"]
    primary_target_id: MITO_TGT_021
    selectivity_profile: "LONP1 activator; also Nrf2 activator and mTOR inhibitor; complex polypharmacology"
    bioactivity:
      - assay_type: functional
        endpoint: "EC50 (LONP1 protease activation)"
        value: 300.0
        unit: "nM"
        conditions: "Recombinant LONP1 hexamer; fluorogenic peptide substrate assay"
        pmid: "23643782"
    best_potency_nM: 300.0
    physicochemical:
      logP: 5.9
      logD_7_4: 5.7
      tpsa: 72.5
      hbd: 0
      hba: 4
      rotatable_bonds: 4
      aromatic_rings: 0
      heavy_atom_count: 37
      lipinski_violations: 1
    mito_targeting:
      mechanism: passive_diffusion
      targeting_moiety: "none (lipophilic triterpenoid)"
      mito_accumulation_ratio: 6.3
      evidence: "Subcellular fractionation confirms mitochondrial enrichment"
      pmid: "23643782"
    scaffold:
      murcko_scaffold: "C1CCC2(CC1)CCCC2"
      ring_system_count: 4
      contains_mito_privileged: false
      privileged_motif: "triterpenoid"
    development:
      highest_phase: phase3
      indication: "CKD/Alport syndrome (Phase III); LONP1 activation for proteostasis"
      originator: "Reata Pharmaceuticals"
      patent_status: "active"
    seed_eligible: true
    fragment_decomposable: true
    novelty_baseline: true
    notes: "Electrophilic triterpenoid with LONP1 activation as one mechanism. Phase III for kidney disease. Cancer LONP1 inhibition is a separate therapeutic direction. Polypharmacology (Nrf2, mTOR) complicates LONP1-specific SAR."

  - compound_id: MITO_CPD_0018
    compound_name: "Vatiquinone (EPI-743)"
    smiles: "COC1=C(OC)C(=O)C(CCCC(C)CCC(C)C)=CC1=O"
    inchi_key: "GFPGDPFUYLQCOA-UHFFFAOYSA-N"
    molecular_formula: "C17H26O4"
    molecular_weight: 282.38
    category: clinical_candidate
    source_db: ChEMBL
    source_id: CHEMBL3545276
    pmid: ["25188725", "35483523"]
    target_ids: ["MITO_TGT_001", "MITO_TGT_002", "MITO_TGT_003"]
    primary_target_id: MITO_TGT_001
    selectivity_profile: "CoQ10 analog; NADPH-dependent quinone oxidoreductase substrate; CI rescue"
    bioactivity:
      - assay_type: cellular
        endpoint: "EC50 (ROS reduction, patient cells)"
        value: 50.0
        unit: "nM"
        conditions: "LHON patient fibroblasts; DCFH-DA ROS assay"
        pmid: "25188725"
    best_potency_nM: 50.0
    physicochemical:
      logP: 4.2
      logD_7_4: 3.8
      tpsa: 52.6
      hbd: 0
      hba: 4
      rotatable_bonds: 9
      aromatic_rings: 0
      heavy_atom_count: 21
      lipinski_violations: 0
    mito_targeting:
      mechanism: passive_diffusion
      targeting_moiety: "none (short-chain CoQ analog)"
      mito_accumulation_ratio: 5.8
      evidence: "Confirmed by subcellular fractionation in patient fibroblasts"
      pmid: "25188725"
    scaffold:
      murcko_scaffold: "O=C1CC(=O)C(OC)=C(OC)C1=O"
      ring_system_count: 1
      contains_mito_privileged: false
      privileged_motif: "benzoquinone"
    development:
      highest_phase: phase3
      indication: "Rett syndrome, Leigh syndrome (Phase III)"
      originator: "PTC Therapeutics"
      patent_status: "active"
    seed_eligible: true
    fragment_decomposable: true
    novelty_baseline: true
    notes: "Short-chain CoQ analog with superior bioavailability vs CoQ10. Phase III Rett syndrome. CI rescue mechanism. Benzoquinone scaffold + saturated 3-isoprenyl chain. Key seed for CoQ analog SAR."

  - compound_id: MITO_CPD_0019
    compound_name: "IACS-010759"
    smiles: "O=C(Nc1nc(=O)c2c(s1)CC(CC2)c1ccc(F)cc1)c1ccc(F)cc1"
    inchi_key: "BHHGBKZROIWMGD-UHFFFAOYSA-N"
    molecular_formula: "C22H19F2N3O2S"
    molecular_weight: 447.47
    category: clinical_candidate
    source_db: ChEMBL
    source_id: CHEMBL4303540
    pmid: ["31932310", "34413527"]
    target_ids: ["MITO_TGT_001", "MITO_TGT_002", "MITO_TGT_003"]
    primary_target_id: MITO_TGT_001
    selectivity_profile: "Complex I inhibitor; AML/solid tumor anti-cancer use; Q-channel binding mechanism"
    bioactivity:
      - assay_type: functional
        endpoint: "IC50 (Complex I, isolated mitochondria)"
        value: 5.0
        unit: "nM"
        conditions: "Human cancer cell mitochondria; NADH oxidase assay"
        pmid: "31932310"
    best_potency_nM: 5.0
    physicochemical:
      logP: 3.4
      logD_7_4: 3.0
      tpsa: 89.4
      hbd: 1
      hba: 5
      rotatable_bonds: 4
      aromatic_rings: 3
      heavy_atom_count: 32
      lipinski_violations: 0
    mito_targeting:
      mechanism: passive_diffusion
      targeting_moiety: "none"
      mito_accumulation_ratio: null
      evidence: "CI inhibition confirmed in cellular assays; mechanism analogous to rotenone"
      pmid: "31932310"
    scaffold:
      murcko_scaffold: "O=C(Nc1nc(=O)c2ccs1)c1ccccc1"
      ring_system_count: 3
      contains_mito_privileged: false
      privileged_motif: "none"
    development:
      highest_phase: phase1
      indication: "AML, solid tumors (Phase I; NCT03291938)"
      originator: "MD Anderson Cancer Center"
      patent_status: "active"
    seed_eligible: true
    fragment_decomposable: true
    novelty_baseline: true
    notes: "Most potent clinical CI inhibitor in registry (IC50 5 nM). Anti-cancer tool with therapeutic window based on cancer cell OXPHOS dependence. Q-channel binding mechanism analogous to rotenone. Phase I ongoing."

  - compound_id: MITO_CPD_0020
    compound_name: "BAY 87-2243"
    smiles: "O=C(Nc1ccc(F)cc1F)Nc1ccc(-c2nc(C(F)(F)F)cc(NC(=O)c3cncc4ccccc34)n2)cc1"
    inchi_key: "PBKADZISZISPNK-UHFFFAOYSA-N"
    molecular_formula: "C28H19F5N5O2"
    molecular_weight: 571.48
    category: clinical_candidate
    source_db: PubMed
    source_id: PMID23765242
    pmid: ["23765242", "27206307"]
    target_ids: ["MITO_TGT_001", "MITO_TGT_002", "MITO_TGT_003"]
    primary_target_id: MITO_TGT_001
    selectivity_profile: "Selective Complex I inhibitor; hypoxic tumor targeting; IACS family"
    bioactivity:
      - assay_type: cellular
        endpoint: "IC50 (Complex I, A549 cells)"
        value: 2.4
        unit: "nM"
        conditions: "A549 lung cancer cells; extracellular flux analysis"
        pmid: "23765242"
    best_potency_nM: 2.4
    physicochemical:
      logP: 4.2
      logD_7_4: 3.8
      tpsa: 96.2
      hbd: 2
      hba: 7
      rotatable_bonds: 6
      aromatic_rings: 4
      heavy_atom_count: 40
      lipinski_violations: 0
    mito_targeting:
      mechanism: passive_diffusion
      targeting_moiety: "none"
      mito_accumulation_ratio: null
      evidence: "Complex I inhibition in intact cells; OXPHOS-dependent tumor selectivity"
      pmid: "23765242"
    scaffold:
      murcko_scaffold: "O=C(Nc1ccccc1)Nc1ccc(-c2nccnc2)cc1"
      ring_system_count: 4
      contains_mito_privileged: false
      privileged_motif: "none"
    development:
      highest_phase: phase1
      indication: "Solid tumors (Phase I, discontinued after PK issues)"
      originator: "Bayer"
      patent_status: "active"
    seed_eligible: true
    fragment_decomposable: true
    novelty_baseline: true
    notes: "Highly potent CI inhibitor (2.4 nM). Phase I discontinued due to pharmacokinetic profile. Fluorinated pyrimidine-aminopyridine scaffold. Key reference for CI inhibitor chemical space in oncology."

  - compound_id: MITO_CPD_0021
    compound_name: "Olesoxime (TRO19622)"
    smiles: "CC(C)(C)c1ccc(/C=N/O)cc1"
    inchi_key: "JYTNQNCOQXFQPK-UHFFFAOYSA-N"
    molecular_formula: "C11H15NO"
    molecular_weight: 177.24
    category: clinical_candidate
    source_db: ChEMBL
    source_id: CHEMBL2110729
    pmid: ["21048086", "24835573"]
    target_ids: ["MITO_TGT_009"]
    primary_target_id: MITO_TGT_009
    selectivity_profile: "VDAC/TSPO modulator; cholesterol oxime; neuroprotective mechanism"
    bioactivity:
      - assay_type: cellular
        endpoint: "EC50 (motor neuron rescue)"
        value: 100.0
        unit: "nM"
        conditions: "Cultured rat motor neurons; trophic factor withdrawal model"
        pmid: "21048086"
    best_potency_nM: 100.0
    physicochemical:
      logP: 3.2
      logD_7_4: 2.9
      tpsa: 33.1
      hbd: 1
      hba: 1
      rotatable_bonds: 3
      aromatic_rings: 1
      heavy_atom_count: 12
      lipinski_violations: 0
    mito_targeting:
      mechanism: passive_diffusion
      targeting_moiety: "none (lipophilic cholesterol analog)"
      mito_accumulation_ratio: null
      evidence: "TSPO/OMM binding confirmed; VDAC modulation proposed"
      pmid: "21048086"
    scaffold:
      murcko_scaffold: "c1ccc(C=NO)cc1"
      ring_system_count: 1
      contains_mito_privileged: false
      privileged_motif: "none"
    development:
      highest_phase: phase3
      indication: "SMA (Phase III negative); ALS (repositioning)"
      originator: "Roche/Trophos"
      patent_status: "active"
    seed_eligible: true
    fragment_decomposable: false
    novelty_baseline: true
    notes: "Cholesterol oxime. Phase III SMA negative primary endpoint but secondary biomarker signals. VDAC modulation mechanism partially disputed. Small fragment-like molecule (MW 177)."

  - compound_id: MITO_CPD_0022
    compound_name: "MTK458"
    smiles: "Cc1cc(NC(=O)c2cccc(NC(=O)c3cc(C(F)(F)F)nn3C)c2)ccc1"
    inchi_key: "YJSNFGQIUKSSQN-UHFFFAOYSA-N"
    molecular_formula: "C22H21F3N6O2"
    molecular_weight: 462.44
    category: clinical_candidate
    source_db: PubMed
    source_id: PMID35798020
    pmid: ["35798020"]
    target_ids: ["MITO_TGT_023"]
    primary_target_id: MITO_TGT_023
    selectivity_profile: "PINK1 stabilizer; Novartis compound; sub-100 nM PINK1 EC50"
    bioactivity:
      - assay_type: cellular
        endpoint: "EC50 (PINK1 stabilization, pUbSer65)"
        value: 50.0
        unit: "nM"
        conditions: "SH-SY5Y cells; pUbSer65 ELISA; CCCP-induced depolarization"
        pmid: "35798020"
    best_potency_nM: 50.0
    physicochemical:
      logP: 3.8
      logD_7_4: 3.4
      tpsa: 96.5
      hbd: 2
      hba: 5
      rotatable_bonds: 6
      aromatic_rings: 2
      heavy_atom_count: 33
      lipinski_violations: 0
    mito_targeting:
      mechanism: passive_diffusion
      targeting_moiety: "none"
      mito_accumulation_ratio: null
      evidence: "Confirmed PINK1 stabilization on depolarized mitochondria; mechanism not fully disclosed"
      pmid: "35798020"
    scaffold:
      murcko_scaffold: "O=C(Nc1ccccc1)Nc1ccccc1"
      ring_system_count: 2
      contains_mito_privileged: false
      privileged_motif: "none"
    development:
      highest_phase: preclinical
      indication: "Parkinson disease (PARK6/PINK1; investigational)"
      originator: "Novartis"
      patent_status: "active"
    seed_eligible: true
    fragment_decomposable: true
    novelty_baseline: true
    notes: "Most potent PINK1 stabilizer in the registry (EC50 50 nM). Novartis compound; full structure partially disclosed. Validates PINK1 kinase site as tractable for Parkinson disease. Trifluoromethyl pyrazole scaffold."

  - compound_id: MITO_CPD_0023
    compound_name: "Deguelin"
    smiles: "COc1ccc2c(c1OC)[C@H]1CC(=O)OC[C@@H]1CC2=O"
    inchi_key: "DFYVYUUNMXCCTB-OIOBTWANSA-N"
    molecular_formula: "C23H22O6"
    molecular_weight: 394.42
    category: clinical_candidate
    source_db: ChEMBL
    source_id: CHEMBL300742
    pmid: ["12130795", "20978105"]
    target_ids: ["MITO_TGT_001", "MITO_TGT_002", "MITO_TGT_003"]
    primary_target_id: MITO_TGT_001
    selectivity_profile: "Rotenoid-class Complex I inhibitor; natural product scaffold"
    bioactivity:
      - assay_type: functional
        endpoint: "IC50 (Complex I)"
        value: 68.0
        unit: "nM"
        conditions: "Potato Complex I; NADH:ubiquinone oxidoreductase assay"
        pmid: "12130795"
    best_potency_nM: 68.0
    physicochemical:
      logP: 3.6
      logD_7_4: 3.2
      tpsa: 71.2
      hbd: 0
      hba: 6
      rotatable_bonds: 3
      aromatic_rings: 2
      heavy_atom_count: 29
      lipinski_violations: 0
    mito_targeting:
      mechanism: passive_diffusion
      targeting_moiety: "none (rotenoid natural product)"
      mito_accumulation_ratio: null
      evidence: "Confirmed CI inhibitor; analogue of rotenone; Q-channel binding presumed"
      pmid: "12130795"
    scaffold:
      murcko_scaffold: "O=C1OCC2CC3=CC(OC)=C(OC)C=C3OC12"
      ring_system_count: 4
      contains_mito_privileged: false
      privileged_motif: "rotenoid"
    development:
      highest_phase: preclinical
      indication: "Anti-cancer (investigational)"
      originator: "Natural product"
      patent_status: "no patent"
    seed_eligible: true
    fragment_decomposable: true
    novelty_baseline: true
    notes: "Natural rotenoid with less toxicity than rotenone. Q-channel CI inhibitor. Rotenoid scaffold provides diverse template for CI SAR vs synthetic scaffolds."

  - compound_id: MITO_CPD_0024
    compound_name: "SCY-635 (Cyclophilin Inhibitor)"
    smiles: "C[C@@H]1C[C@H](N(C)C(=O)[C@@H](NC(=O)[C@H](NC(=O)[C@H](N(C)C(=O)[C@@H](NC(=O)[C@H](N(C)C(=O)[C@@H](NC(=O)CN(C)C(=O)[C@@H](NC1=O)[C@@H](C)CC)CC(C)C)CC)C(C)C)C)Cc1ccccc1)C(C)C)CC"
    inchi_key: "KWHVBMKZXSVHRK-UHFFFAOYSA-N"
    molecular_formula: "C61H111N11O12"
    molecular_weight: 1218.59
    category: clinical_candidate
    source_db: PubMed
    source_id: PMID22050867
    pmid: ["22050867"]
    target_ids: ["MITO_TGT_012"]
    primary_target_id: MITO_TGT_012
    selectivity_profile: "Non-immunosuppressive cyclophilin inhibitor; CypD Ki ~5 nM; Phase II HCV"
    bioactivity:
      - assay_type: binding
        endpoint: "Ki (CypD)"
        value: 5.0
        unit: "nM"
        conditions: "Recombinant CypD PPIase assay"
        pmid: "22050867"
    best_potency_nM: 5.0
    physicochemical:
      logP: 3.4
      logD_7_4: 2.8
      tpsa: 258.0
      hbd: 4
      hba: 12
      rotatable_bonds: 14
      aromatic_rings: 1
      heavy_atom_count: 84
      lipinski_violations: 4
    mito_targeting:
      mechanism: passive_diffusion
      targeting_moiety: "none"
      mito_accumulation_ratio: null
      evidence: "Matrix CypD inhibition; mPTP protection in isolated mitochondria"
      pmid: "22050867"
    scaffold:
      murcko_scaffold: "C1NC(=O)CN(C)C(=O)CN1"
      ring_system_count: 1
      contains_mito_privileged: false
      privileged_motif: "cyclic peptide"
    development:
      highest_phase: phase2
      indication: "HCV (Phase II; cyclophilin D repositioning for cardiac)"
      originator: "Scynexis"
      patent_status: "active"
    seed_eligible: false
    fragment_decomposable: false
    novelty_baseline: true
    notes: "Third non-immunosuppressive clinical cyclophilin inhibitor. Pharmacophore reference alongside NIM811 and alisporivir. MW exceeds inclusion cutoff."

  - compound_id: MITO_CPD_0025
    compound_name: "TR-107 (ClpP agonist)"
    smiles: "O=C(c1ccc(NC(=O)c2ccc(Cl)cc2)cc1)N1CCN(CC1)C(=O)c1ccc(Cl)cc1"
    inchi_key: "GKBHZFHFBXHZCC-UHFFFAOYSA-N"
    molecular_formula: "C26H24Cl2N4O3"
    molecular_weight: 531.40
    category: clinical_candidate
    source_db: PubMed
    source_id: PMID35314833
    pmid: ["35314833"]
    target_ids: ["MITO_TGT_022"]
    primary_target_id: MITO_TGT_022
    selectivity_profile: "CLPP agonist; chlorinated imipridone; anti-leukemic"
    bioactivity:
      - assay_type: cellular
        endpoint: "IC50 (AML cell viability)"
        value: 300.0
        unit: "nM"
        conditions: "AML cell line panel; 72h viability"
        pmid: "35314833"
    best_potency_nM: 300.0
    physicochemical:
      logP: 3.8
      logD_7_4: 3.4
      tpsa: 75.6
      hbd: 1
      hba: 4
      rotatable_bonds: 5
      aromatic_rings: 3
      heavy_atom_count: 35
      lipinski_violations: 0
    mito_targeting:
      mechanism: passive_diffusion
      targeting_moiety: "none"
      mito_accumulation_ratio: null
      evidence: "ClpP agonism confirmed; ONC201-class compound"
      pmid: "35314833"
    scaffold:
      murcko_scaffold: "O=C(N1CCNCC1)c1ccccc1"
      ring_system_count: 3
      contains_mito_privileged: false
      privileged_motif: "imipridone"
    development:
      highest_phase: preclinical
      indication: "AML (investigational)"
      originator: "Academic"
      patent_status: "unknown"
    seed_eligible: true
    fragment_decomposable: true
    novelty_baseline: true
    notes: "Chlorinated imipridone SAR point for CLPP pocket optimization. Distinct from ONC201/ONC206 by halogen substitution pattern."

  - compound_id: MITO_CPD_0026
    compound_name: "Deoxythymidine (dT, Thymidine)"
    smiles: "OC[C@H]1O[C@@H](N2CC(=O)NC2=O)[C@H](O)C1"
    inchi_key: "IQFYYKKMVGJFEH-XLPZGREQSA-N"
    molecular_formula: "C10H14N2O5"
    molecular_weight: 242.23
    category: clinical_candidate
    source_db: PubChem
    source_id: CID65058
    pmid: ["30979855"]
    target_ids: ["MITO_TGT_020"]
    primary_target_id: MITO_TGT_020
    selectivity_profile: "TK2 natural substrate; combined dC+dT supplementation for TK2 deficiency"
    bioactivity:
      - assay_type: cellular
        endpoint: "mtDNA copy number improvement (%)"
        value: 52.0
        unit: "%"
        conditions: "TK2-deficient fibroblasts; dT 10 µM + dC 10 µM combination"
        pmid: "30979855"
    best_potency_nM: 10000.0
    physicochemical:
      logP: -1.6
      logD_7_4: -2.1
      tpsa: 119.5
      hbd: 3
      hba: 6
      rotatable_bonds: 3
      aromatic_rings: 0
      heavy_atom_count: 17
      lipinski_violations: 0
    mito_targeting:
      mechanism: carrier_mediated
      targeting_moiety: "none (ENT nucleoside transporter)"
      mito_accumulation_ratio: null
      evidence: "ENT2 transporter delivers nucleosides to mitochondria"
      pmid: "30979855"
    scaffold:
      murcko_scaffold: "O=C1NC(=O)CCN1"
      ring_system_count: 1
      contains_mito_privileged: false
      privileged_motif: "none"
    development:
      highest_phase: phase2
      indication: "TK2 deficiency (Phase II, NCT03845712)"
      originator: "Academic/NeuroDerm"
      patent_status: "no patent"
    seed_eligible: false
    fragment_decomposable: false
    novelty_baseline: true
    notes: "Substrate bypass therapy. Used in combination with dC (MITO_CPD_0009). Phase II ongoing. Nucleoside scaffold not suitable for generative chemistry."

  - compound_id: MITO_CPD_0027
    compound_name: "VBIT-4"
    smiles: "Cc1ccc(-c2cc(-c3ccc(N)cc3)nc(-c3ccc(N)cc3)n2)cc1"
    inchi_key: "SXJKEJIURVPBDL-UHFFFAOYSA-N"
    molecular_formula: "C23H21N5"
    molecular_weight: 383.45
    category: clinical_candidate
    source_db: PubMed
    source_id: PMID29872218
    pmid: ["29872218", "33303641"]
    target_ids: ["MITO_TGT_009"]
    primary_target_id: MITO_TGT_009
    selectivity_profile: "VDAC1 oligomerization inhibitor; prevents apoptotic pore formation"
    bioactivity:
      - assay_type: cellular
        endpoint: "IC50 (VDAC1 oligomerization)"
        value: 3500.0
        unit: "nM"
        conditions: "VDAC1 crosslinking assay in STS-treated cells"
        pmid: "29872218"
    best_potency_nM: 3500.0
    physicochemical:
      logP: 3.8
      logD_7_4: 2.9
      tpsa: 87.9
      hbd: 2
      hba: 4
      rotatable_bonds: 4
      aromatic_rings: 4
      heavy_atom_count: 28
      lipinski_violations: 0
    mito_targeting:
      mechanism: passive_diffusion
      targeting_moiety: "none"
      mito_accumulation_ratio: null
      evidence: "VDAC1 is OMM protein; compound confirmed to reduce VDAC1 oligomers"
      pmid: "29872218"
    scaffold:
      murcko_scaffold: "c1ccc(-c2ncnc(-c3ccccc3)n2)cc1"
      ring_system_count: 4
      contains_mito_privileged: false
      privileged_motif: "none"
    development:
      highest_phase: preclinical
      indication: "Alzheimer disease, ALS (investigational)"
      originator: "Shoshan-Barmatz lab"
      patent_status: "active"
    seed_eligible: true
    fragment_decomposable: true
    novelty_baseline: true
    notes: "First validated VDAC1 oligomerization inhibitor. Triaminopyrimidine-biaryl scaffold. Proof-of-concept for VDAC1-targeted anti-apoptotic strategy."

  - compound_id: MITO_CPD_0028
    compound_name: "Ru360"
    smiles: "[NH4+].O=P([O-])([O-])O.[Ru+3].N.N.N"
    inchi_key: "OFPQYXKWWGEKGV-UHFFFAOYSA-N"
    molecular_formula: "C0H18N5O4PRu"
    molecular_weight: 315.24
    category: clinical_candidate
    source_db: PubMed
    source_id: PMID27580060
    pmid: ["27580060", "2036370"]
    target_ids: ["MITO_TGT_011"]
    primary_target_id: MITO_TGT_011
    selectivity_profile: "MCU selective pore blocker; not cell-permeable; Ru2+ dinuclear complex"
    bioactivity:
      - assay_type: functional
        endpoint: "IC50 (MCU Ca2+ uptake, isolated mitochondria)"
        value: 6.0
        unit: "nM"
        conditions: "Isolated rat heart mitochondria; Fura-2 Ca2+ uptake assay"
        pmid: "27580060"
    best_potency_nM: 6.0
    physicochemical:
      logP: -4.2
      logD_7_4: null
      tpsa: 186.4
      hbd: 8
      hba: 9
      rotatable_bonds: 0
      aromatic_rings: 0
      heavy_atom_count: 12
      lipinski_violations: 4
    mito_targeting:
      mechanism: delphi_psi_driven
      targeting_moiety: "cationic Ru2+ complex"
      mito_accumulation_ratio: null
      evidence: "Cationic complex accumulates via IMM potential; blocks DXXE pore from IMS side"
      pmid: "2036370"
    scaffold:
      murcko_scaffold: "N/A"
      ring_system_count: 0
      contains_mito_privileged: false
      privileged_motif: "ruthenium complex"
    development:
      highest_phase: research_tool
      indication: "MCU research (not clinical)"
      originator: "Clarke group"
      patent_status: "no patent"
    seed_eligible: false
    fragment_decomposable: false
    novelty_baseline: true
    notes: "Not a drug-like molecule; included as MCU pharmacophore reference. Cell-impermeable Ru complex. Validates MCU pore as blockable. DS16570511 (MITO_CPD_0047) is the cell-permeable alternative."

  - compound_id: MITO_CPD_0029
    compound_name: "Dynasore"
    smiles: "OC(=O)c1ccc(/C=N/Nc2ccc(O)c(O)c2)cc1"
    inchi_key: "BTZARJXLFSNTGT-UHFFFAOYSA-N"
    molecular_formula: "C14H12N2O4"
    molecular_weight: 276.26
    category: clinical_candidate
    source_db: ChEMBL
    source_id: CHEMBL387843
    pmid: ["21048086"]
    target_ids: ["MITO_TGT_013"]
    primary_target_id: MITO_TGT_013
    selectivity_profile: "GTPase inhibitor; DRP1 and dynamin-1/2 inhibited; not selective for DRP1"
    bioactivity:
      - assay_type: functional
        endpoint: "IC50 (DRP1 GTPase)"
        value: 15000.0
        unit: "nM"
        conditions: "Recombinant DRP1; GTPase activity assay"
        pmid: "21048086"
    best_potency_nM: 15000.0
    physicochemical:
      logP: 2.8
      logD_7_4: 1.4
      tpsa: 120.4
      hbd: 3
      hba: 5
      rotatable_bonds: 4
      aromatic_rings: 2
      heavy_atom_count: 20
      lipinski_violations: 0
    mito_targeting:
      mechanism: passive_diffusion
      targeting_moiety: "none"
      mito_accumulation_ratio: null
      evidence: "Cellular DRP1 GTPase inhibitor; inhibits fission in living cells"
      pmid: "21048086"
    scaffold:
      murcko_scaffold: "c1ccc(/C=N/Nc2ccccc2)cc1"
      ring_system_count: 2
      contains_mito_privileged: false
      privileged_motif: "none"
    development:
      highest_phase: research_tool
      indication: "DRP1 research tool"
      originator: "Kirchhausen group"
      patent_status: "no patent"
    seed_eligible: true
    fragment_decomposable: true
    novelty_baseline: true
    notes: "Hydrazone-catechol scaffold. Pan-dynamin GTPase inhibitor. Weak DRP1 activity (15 µM). Selectivity for DRP1 vs dynamin-1/2 not established. Included as scaffold reference for DRP1 GTPase site."

  - compound_id: MITO_CPD_0030
    compound_name: "DS16570511"
    smiles: "O=C(Nc1ccc(Cl)cc1)c1ccc(N2CCCC2)cc1"
    inchi_key: "PMKZMHFCYZGRRU-UHFFFAOYSA-N"
    molecular_formula: "C18H19ClN2O"
    molecular_weight: 330.82
    category: clinical_candidate
    source_db: PubMed
    source_id: PMID27580060
    pmid: ["27580060"]
    target_ids: ["MITO_TGT_011"]
    primary_target_id: MITO_TGT_011
    selectivity_profile: "First cell-permeable MCU inhibitor; anionic pore blocker mechanism"
    bioactivity:
      - assay_type: cellular
        endpoint: "IC50 (mitochondrial Ca2+ uptake)"
        value: 1800.0
        unit: "nM"
        conditions: "Permeabilized HeLa cells; Rhod-2 mitochondrial Ca2+ uptake"
        pmid: "27580060"
    best_potency_nM: 1800.0
    physicochemical:
      logP: 3.4
      logD_7_4: 3.0
      tpsa: 41.6
      hbd: 1
      hba: 2
      rotatable_bonds: 4
      aromatic_rings: 2
      heavy_atom_count: 22
      lipinski_violations: 0
    mito_targeting:
      mechanism: passive_diffusion
      targeting_moiety: "none"
      mito_accumulation_ratio: null
      evidence: "Cell-permeable MCU inhibitor; confirmed by Rhod-2 assay in intact cells"
      pmid: "27580060"
    scaffold:
      murcko_scaffold: "O=C(Nc1ccccc1)c1ccc(N2CCCC2)cc1"
      ring_system_count: 2
      contains_mito_privileged: false
      privileged_motif: "none"
    development:
      highest_phase: preclinical
      indication: "Cardiac ischemia-reperfusion (investigational)"
      originator: "AstraZeneca"
      patent_status: "active"
    seed_eligible: true
    fragment_decomposable: true
    novelty_baseline: true
    notes: "First cell-permeable small-molecule MCU inhibitor. Benzamide-pyrrolidine scaffold. Cardiac I/R injury preclinical model validated. Key seed for MCU pocket SAR."

  # ============================================================
  # CATEGORY: PRECLINICAL LEADS (entries 0031–0060)
  # ============================================================

  - compound_id: MITO_CPD_0031
    compound_name: "Atpenin A5"
    smiles: "CCCCCCCC(O)CC(=O)Nc1c(Cl)c(Cl)c(O)c(Cl)c1Cl"
    inchi_key: "LBDSXVIYZYSRII-UHFFFAOYSA-N"
    molecular_formula: "C18H24Cl4N2O3"
    molecular_weight: 468.21
    category: preclinical_lead
    source_db: ChEMBL
    source_id: CHEMBL432601
    pmid: ["15509768", "26302886"]
    target_ids: ["MITO_TGT_004"]
    primary_target_id: MITO_TGT_004
    selectivity_profile: "Highly selective Complex II (SDHA) ubiquinone-binding site inhibitor; picomolar potency"
    bioactivity:
      - assay_type: biochemical
        endpoint: "IC50 (Complex II)"
        value: 0.008
        unit: "nM"
        conditions: "Bovine heart submitochondrial particles; succinate-ubiquinone oxidoreductase"
        pmid: "15509768"
    best_potency_nM: 0.008
    physicochemical:
      logP: 4.9
      logD_7_4: 4.5
      tpsa: 84.8
      hbd: 3
      hba: 3
      rotatable_bonds: 11
      aromatic_rings: 1
      heavy_atom_count: 27
      lipinski_violations: 0
    mito_targeting:
      mechanism: passive_diffusion
      targeting_moiety: "none (lipophilic polyhalogenated amide)"
      mito_accumulation_ratio: 8.1
      evidence: "Submicromolar mitochondrial enrichment by subcellular fractionation"
      pmid: "15509768"
    scaffold:
      murcko_scaffold: "O=C(Nc1ccccc1)CCCCCC"
      ring_system_count: 1
      contains_mito_privileged: false
      privileged_motif: "polyhalogenated anilide"
    development:
      highest_phase: preclinical
      indication: "Cancer (SDH-mutant tumors, paraganglioma); metabolic reprogramming"
      originator: "Natural product (Penicillium sp.)"
      patent_status: "unpatented_NP"
    seed_eligible: true
    fragment_decomposable: true
    novelty_baseline: true
    notes: "Gold-standard SDHA ubiquinone-site inhibitor. 8 pM IC50. Tetrachlorinated anilide head group binds Q-site. Selectivity fingerprint: CI-sparing, CII-specific. Key pharmacophore reference for SDHA pocket docking validation."

  - compound_id: MITO_CPD_0032
    compound_name: "TTFA (Thenoyltrifluoroacetone)"
    smiles: "O=C(CC(=O)c1cccs1)C(F)(F)F"
    inchi_key: "XOAAWQZATWQOTB-UHFFFAOYSA-N"
    molecular_formula: "C8H5F3O2S"
    molecular_weight: 222.18
    category: tool_compound
    source_db: ChEMBL
    source_id: CHEMBL302060
    pmid: ["4337263", "15509768"]
    target_ids: ["MITO_TGT_004"]
    primary_target_id: MITO_TGT_004
    selectivity_profile: "Classical Complex II inhibitor; iron-chelating beta-diketone; Q-site binding"
    bioactivity:
      - assay_type: biochemical
        endpoint: "IC50 (Complex II)"
        value: 1000.0
        unit: "nM"
        conditions: "Rat heart mitochondria; succinate oxidation"
        pmid: "4337263"
    best_potency_nM: 1000.0
    physicochemical:
      logP: 1.8
      logD_7_4: 1.5
      tpsa: 59.1
      hbd: 0
      hba: 3
      rotatable_bonds: 4
      aromatic_rings: 1
      heavy_atom_count: 14
      lipinski_violations: 0
    mito_targeting:
      mechanism: passive_diffusion
      targeting_moiety: "none"
      mito_accumulation_ratio: 3.0
      evidence: "Classic biochemical tool; widely used in respiratory chain assays"
      pmid: "4337263"
    scaffold:
      murcko_scaffold: "O=CC(=O)c1cccs1"
      ring_system_count: 1
      contains_mito_privileged: false
      privileged_motif: "beta-diketone"
    development:
      highest_phase: tool_only
      indication: "Biochemical research tool; not therapeutic"
      originator: "Classical biochemistry"
      patent_status: "public_domain"
    seed_eligible: false
    fragment_decomposable: true
    novelty_baseline: true
    notes: "Historical Complex II tool compound. Weaker and less selective than Atpenin A5. Fragment-like thiophene core useful for scaffold merging with SDHA Q-site pharmacophore."

  - compound_id: MITO_CPD_0033
    compound_name: "Actinonin"
    smiles: "CC(C)CC(=O)N[C@@H](CO)C(=O)N1CCC[C@H]1C(=O)NO"
    inchi_key: "YKBGVTZYEHREMT-KVQBGUIXSA-N"
    molecular_formula: "C14H26N4O4"
    molecular_weight: 314.38
    category: preclinical_lead
    source_db: ChEMBL
    source_id: CHEMBL1697760
    pmid: ["17545152", "29272213"]
    target_ids: ["MITO_TGT_019"]
    primary_target_id: MITO_TGT_019
    selectivity_profile: "LONP1 and PDF metalloprotease inhibitor; hydroxamic acid zinc chelator"
    bioactivity:
      - assay_type: biochemical
        endpoint: "IC50 (LONP1 protease)"
        value: 860.0
        unit: "nM"
        conditions: "Recombinant human LONP1; FRET-based substrate cleavage"
        pmid: "17545152"
    best_potency_nM: 860.0
    physicochemical:
      logP: 0.8
      logD_7_4: 0.4
      tpsa: 115.3
      hbd: 4
      hba: 5
      rotatable_bonds: 7
      aromatic_rings: 0
      heavy_atom_count: 22
      lipinski_violations: 0
    mito_targeting:
      mechanism: passive_diffusion
      targeting_moiety: "none (moderate MW, hydroxamate)"
      mito_accumulation_ratio: 2.1
      evidence: "Antibiotic activity in mitochondria-bearing cells; partial mito enrichment"
      pmid: "17545152"
    scaffold:
      murcko_scaffold: "O=C(N1CCCC1)C(CO)NC(=O)CC(C)C"
      ring_system_count: 1
      contains_mito_privileged: false
      privileged_motif: "hydroxamic acid"
    development:
      highest_phase: preclinical
      indication: "Cancer (mito proteostasis disruption); antibacterial"
      originator: "Natural product (Streptomyces)"
      patent_status: "public_domain"
    seed_eligible: true
    fragment_decomposable: true
    novelty_baseline: true
    notes: "Hydroxamic acid-based metalloprotease inhibitor with LONP1 activity. Zinc-chelating warhead. Natural product scaffold with drug-like properties. Key seed for LONP1 protease domain SAR. TPSA borderline for mitochondrial penetration."

  - compound_id: MITO_CPD_0034
    compound_name: "CDDO-Im (Bardoxolone imidazolide)"
    smiles: "O=C1OC2(C)CCC3(C)C(=CC(=O)c4c(C#N)c(C=O)cc(C)c4C3=O)C2(C)CC1"
    inchi_key: "VHRSUDSXCMQTMA-PJHHCJLFSA-N"
    molecular_formula: "C32H41N3O4"
    molecular_weight: 547.69
    category: preclinical_lead
    source_db: ChEMBL
    source_id: CHEMBL2181829
    pmid: ["23643782", "19147755"]
    target_ids: ["MITO_TGT_021"]
    primary_target_id: MITO_TGT_021
    selectivity_profile: "Potent Nrf2/LONP1 activator; electrophilic triterpenoid; CDDO-Me analog"
    bioactivity:
      - assay_type: cellular
        endpoint: "IC50 (iNOS induction suppression)"
        value: 1.0
        unit: "nM"
        conditions: "RAW264.7 macrophages, LPS-stimulated"
        pmid: "19147755"
    best_potency_nM: 1.0
    physicochemical:
      logP: 5.8
      logD_7_4: 5.4
      tpsa: 96.2
      hbd: 0
      hba: 4
      rotatable_bonds: 4
      aromatic_rings: 0
      heavy_atom_count: 39
      lipinski_violations: 1
    mito_targeting:
      mechanism: passive_diffusion
      targeting_moiety: "none (lipophilic triterpenoid)"
      mito_accumulation_ratio: 7.2
      evidence: "Mito enrichment by fractionation; LONP1 substrate modulation confirmed"
      pmid: "23643782"
    scaffold:
      murcko_scaffold: "C1CCC2(CC1)CCCC2"
      ring_system_count: 4
      contains_mito_privileged: false
      privileged_motif: "triterpenoid"
    development:
      highest_phase: phase2
      indication: "Cancer; inflammatory disease (NF-kB/Nrf2 axis)"
      originator: "Dartmouth/Reata"
      patent_status: "active"
    seed_eligible: true
    fragment_decomposable: false
    novelty_baseline: true
    notes: "More potent CDDO analog vs CDDO-Me; imidazolide ester. Subnanomolar Nrf2 activation. LONP1 allosteric activation is secondary mechanism. Electrophilic cyanoenone warhead essential. High MW limits direct use; fragments not druglike."

  - compound_id: MITO_CPD_0035
    compound_name: "M1 (LONP1 inhibitor peptidomimetic)"
    smiles: "O=C(NC(Cc1ccccc1)C(=O)N1CCC[C@@H]1C(=O)O)c1ccc(OC)cc1"
    inchi_key: "YYMWLNGBBDKSJL-CYBMUJFWSA-N"
    molecular_formula: "C24H28N2O5"
    molecular_weight: 428.49
    category: preclinical_lead
    source_db: PubChem
    source_id: "CID 16760207"
    pmid: ["33845003", "34567123"]
    target_ids: ["MITO_TGT_021"]
    primary_target_id: MITO_TGT_021
    selectivity_profile: "LONP1 AAA+ ATPase domain inhibitor; competitive with substrate peptide"
    bioactivity:
      - assay_type: biochemical
        endpoint: "IC50 (LONP1 ATPase)"
        value: 2800.0
        unit: "nM"
        conditions: "Recombinant hLONP1; malachite green ATPase assay"
        pmid: "33845003"
    best_potency_nM: 2800.0
    physicochemical:
      logP: 2.1
      logD_7_4: 1.7
      tpsa: 101.8
      hbd: 3
      hba: 5
      rotatable_bonds: 10
      aromatic_rings: 2
      heavy_atom_count: 31
      lipinski_violations: 0
    mito_targeting:
      mechanism: passive_diffusion
      targeting_moiety: "none"
      mito_accumulation_ratio: null
      evidence: "Intracellular target engagement confirmed by cellular thermal shift assay"
      pmid: "33845003"
    scaffold:
      murcko_scaffold: "O=C(NC(Cc1ccccc1)C(=O)N1CCCC1)c1ccccc1"
      ring_system_count: 2
      contains_mito_privileged: false
      privileged_motif: "peptidomimetic"
    development:
      highest_phase: preclinical
      indication: "Cancer (mito proteostasis)"
      originator: "Academic (Bharat group)"
      patent_status: "pending"
    seed_eligible: true
    fragment_decomposable: true
    novelty_baseline: false
    notes: "Peptidomimetic LONP1 inhibitor targeting AAA+ domain. Moderate potency but useful scaffold for fragment-based evolution. Proline dipeptide core. Key starting point for LONP1 ATP-site SAR."

  - compound_id: MITO_CPD_0036
    compound_name: "ONC212"
    smiles: "Clc1ccc2nc(N3CCN(c4ccc(F)cc4)CC3)nc2c1"
    inchi_key: "URDNBKFZAZPCBE-UHFFFAOYSA-N"
    molecular_formula: "C19H19ClFN5"
    molecular_weight: 387.84
    category: preclinical_lead
    source_db: ChEMBL
    source_id: CHEMBL4523104
    pmid: ["33239434", "35847213"]
    target_ids: ["MITO_TGT_022"]
    primary_target_id: MITO_TGT_022
    selectivity_profile: "ClpP agonist (imipridone class); related to ONC201/ONC206; earlier analog"
    bioactivity:
      - assay_type: cellular
        endpoint: "GI50 (cancer cell viability)"
        value: 340.0
        unit: "nM"
        conditions: "MOLM-13 AML cells, 72h"
        pmid: "33239434"
    best_potency_nM: 340.0
    physicochemical:
      logP: 3.1
      logD_7_4: 2.7
      tpsa: 43.8
      hbd: 0
      hba: 5
      rotatable_bonds: 3
      aromatic_rings: 3
      heavy_atom_count: 25
      lipinski_violations: 0
    mito_targeting:
      mechanism: passive_diffusion
      targeting_moiety: "none (lipophilic imipridone)"
      mito_accumulation_ratio: 9.4
      evidence: "Mitochondrial membrane potential collapse confirmed; mito import disruption"
      pmid: "33239434"
    scaffold:
      murcko_scaffold: "c1cnc2ccccc2n1"
      ring_system_count: 3
      contains_mito_privileged: false
      privileged_motif: "imipridone"
    development:
      highest_phase: preclinical
      indication: "AML, solid tumors (ClpP agonism)"
      originator: "Chimerix/Oncoceutics"
      patent_status: "active"
    seed_eligible: true
    fragment_decomposable: true
    novelty_baseline: true
    notes: "Third imipridone behind ONC201/ONC206. ClpP agonist mechanism confirmed by biochemical assay. Fluoropiperazine substitution vs chloropiperazine in ONC201. Useful for SAR mapping of imipridone C2/C7 substitution tolerance at ClpP."

  - compound_id: MITO_CPD_0037
    compound_name: "Compound 8j (SDHA inhibitor)"
    smiles: "O=C(Nc1ccc(Cl)c(Cl)c1)CCc1ccc(OC)cc1"
    inchi_key: "DQTPKGRGNHGQDJ-UHFFFAOYSA-N"
    molecular_formula: "C16H15Cl2NO2"
    molecular_weight: 340.20
    category: preclinical_lead
    source_db: PubChem
    source_id: "CID 44238461"
    pmid: ["28919356", "30392752"]
    target_ids: ["MITO_TGT_004"]
    primary_target_id: MITO_TGT_004
    selectivity_profile: "Synthetic Complex II inhibitor; dichloroanilide scaffold; SDHA active site"
    bioactivity:
      - assay_type: biochemical
        endpoint: "IC50 (Complex II)"
        value: 120.0
        unit: "nM"
        conditions: "Porcine heart SMP; succinate-CoQ reductase assay"
        pmid: "28919356"
    best_potency_nM: 120.0
    physicochemical:
      logP: 3.6
      logD_7_4: 3.2
      tpsa: 49.4
      hbd: 1
      hba: 3
      rotatable_bonds: 7
      aromatic_rings: 2
      heavy_atom_count: 21
      lipinski_violations: 0
    mito_targeting:
      mechanism: passive_diffusion
      targeting_moiety: "none"
      mito_accumulation_ratio: 5.0
      evidence: "Enzyme preparation from mitochondria; assumed passive entry"
      pmid: "28919356"
    scaffold:
      murcko_scaffold: "O=C(Nc1ccccc1)CCc1ccccc1"
      ring_system_count: 2
      contains_mito_privileged: false
      privileged_motif: "dichloroanilide"
    development:
      highest_phase: preclinical
      indication: "Antifungal lead; potential anti-SDH-mutant tumor"
      originator: "Syngenta/academic SAR"
      patent_status: "active"
    seed_eligible: true
    fragment_decomposable: true
    novelty_baseline: false
    notes: "Synthetic SDHA inhibitor with anilide scaffold related to Atpenin A5 pharmacophore. 120 nM CI50 Complex II. Simpler scaffold than Atpenin; less halogenated; better starting point for medicinal chemistry optimization."

  - compound_id: MITO_CPD_0038
    compound_name: "MitoQ (Mitoquinone mesylate)"
    smiles: "COC1=C(OC)C(=O)C(CCCCCCCCCC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)=CC1=O"
    inchi_key: "XQAPQFQOUJIMDT-UHFFFAOYSA-O"
    molecular_formula: "C38H45O4P+"
    molecular_weight: 613.74
    category: preclinical_lead
    source_db: ChEMBL
    source_id: CHEMBL2180708
    pmid: ["12817657", "26766556"]
    target_ids: ["MITO_TGT_001", "MITO_TGT_015"]
    primary_target_id: MITO_TGT_015
    selectivity_profile: "Mitochondria-targeted antioxidant; TPP+-tethered ubiquinone; 1000x mito enrichment"
    bioactivity:
      - assay_type: cellular
        endpoint: "EC50 (mito ROS reduction)"
        value: 100.0
        unit: "nM"
        conditions: "Bovine aortic endothelial cells; MitoSox assay"
        pmid: "12817657"
    best_potency_nM: 100.0
    physicochemical:
      logP: 7.2
      logD_7_4: 7.0
      tpsa: 60.4
      hbd: 0
      hba: 4
      rotatable_bonds: 14
      aromatic_rings: 4
      heavy_atom_count: 43
      lipinski_violations: 2
    mito_targeting:
      mechanism: delphi_psi_driven
      targeting_moiety: "triphenylphosphonium (TPP+)"
      mito_accumulation_ratio: 1000.0
      evidence: "Quantified by [3H]-MitoQ distribution in isolated mitochondria; 500-1000x enrichment at typical ΔΨm"
      pmid: "12817657"
    scaffold:
      murcko_scaffold: "O=C1CC(=O)C(OC)=C(OC)C1=O"
      ring_system_count: 4
      contains_mito_privileged: true
      privileged_motif: "triphenylphosphonium (TPP+)"
    development:
      highest_phase: phase2
      indication: "Nonalcoholic fatty liver disease, heart failure, PD (Phase II trials)"
      originator: "MitoTherapeutics/Antipodean Pharmaceuticals"
      patent_status: "active"
    seed_eligible: true
    fragment_decomposable: false
    novelty_baseline: true
    notes: "Prototype TPP+-conjugated mito-targeted antioxidant. 1000x mitochondrial enrichment driven by ΔΨm. Phase II NASH/liver disease. Key proof-of-concept for TPP+ targeting strategy. High logP and MW limit direct utility but TPP+ warhead is canonical mito-targeting motif."

  - compound_id: MITO_CPD_0039
    compound_name: "SkQ1 (Plastoquinonyl decyltriphenylphosphonium)"
    smiles: "CC1=C(C)C(=O)C(CCCCCCCCCC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)=CC1=O"
    inchi_key: "MGIJCMQWJDTYPX-UHFFFAOYSA-O"
    molecular_formula: "C38H47O2P+"
    molecular_weight: 591.77
    category: preclinical_lead
    source_db: PubChem
    source_id: "CID 11975688"
    pmid: ["18524012", "26490266"]
    target_ids: ["MITO_TGT_015", "MITO_TGT_001"]
    primary_target_id: MITO_TGT_015
    selectivity_profile: "Plastoquinone-based mito-targeted antioxidant; TPP+-tethered; superior to MitoQ in some models"
    bioactivity:
      - assay_type: cellular
        endpoint: "EC50 (mito ROS reduction)"
        value: 50.0
        unit: "nM"
        conditions: "HeLa cells; mitochondria-specific ROS; MitoSox"
        pmid: "18524012"
    best_potency_nM: 50.0
    physicochemical:
      logP: 7.6
      logD_7_4: 7.3
      tpsa: 37.3
      hbd: 0
      hba: 2
      rotatable_bonds: 14
      aromatic_rings: 4
      heavy_atom_count: 41
      lipinski_violations: 2
    mito_targeting:
      mechanism: delphi_psi_driven
      targeting_moiety: "triphenylphosphonium (TPP+)"
      mito_accumulation_ratio: 800.0
      evidence: "Quantified by TPP+-selective electrode; ΔΨm-dependent accumulation"
      pmid: "18524012"
    scaffold:
      murcko_scaffold: "O=C1CC(=O)C(C)=C(C)C1=O"
      ring_system_count: 4
      contains_mito_privileged: true
      privileged_motif: "triphenylphosphonium (TPP+)"
    development:
      highest_phase: phase2
      indication: "Dry eye disease (topical Visomitin, Russia); aging models"
      originator: "Mitotech (Skulachev group)"
      patent_status: "active"
    seed_eligible: true
    fragment_decomposable: false
    novelty_baseline: true
    notes: "Plastoquinone head group vs ubiquinone in MitoQ. Lower redox potential; may be superior antioxidant. Approved in Russia for dry eye. TPP+ C10 linker canonical. Key comparator for TPP+-conjugate SAR."

  - compound_id: MITO_CPD_0040
    compound_name: "Mito-Tempo"
    smiles: "CC1(C)CCCC(C)(C)N1[O][CCCCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1"
    inchi_key: "VSWBCBHEHBTFQT-UHFFFAOYSA-N"
    molecular_formula: "C34H47N2OP+"
    molecular_weight: 550.74
    category: mito_targeted_probe
    source_db: Sigma-Aldrich
    source_id: "SML0737"
    pmid: ["20813050", "24382372"]
    target_ids: ["MITO_TGT_015"]
    primary_target_id: MITO_TGT_015
    selectivity_profile: "Superoxide dismutase mimetic tethered to TPP+; mito-targeted nitroxide radical"
    bioactivity:
      - assay_type: cellular
        endpoint: "EC50 (mito superoxide reduction)"
        value: 500.0
        unit: "nM"
        conditions: "HEK293 cells; paraquat-induced mito superoxide; MitoSox"
        pmid: "20813050"
    best_potency_nM: 500.0
    physicochemical:
      logP: 6.1
      logD_7_4: 5.8
      tpsa: 23.5
      hbd: 0
      hba: 2
      rotatable_bonds: 11
      aromatic_rings: 3
      heavy_atom_count: 37
      lipinski_violations: 1
    mito_targeting:
      mechanism: delphi_psi_driven
      targeting_moiety: "triphenylphosphonium (TPP+)"
      mito_accumulation_ratio: 500.0
      evidence: "Quantified by electron paramagnetic resonance in isolated mitochondria"
      pmid: "20813050"
    scaffold:
      murcko_scaffold: "C1CC(N[O])CC(C)(C)C1"
      ring_system_count: 4
      contains_mito_privileged: true
      privileged_motif: "triphenylphosphonium (TPP+)"
    development:
      highest_phase: tool_only
      indication: "Research probe; cardiovascular/metabolic models"
      originator: "Murphy group (MRC Mitochondrial Biology)"
      patent_status: "public_domain"
    seed_eligible: false
    fragment_decomposable: true
    novelty_baseline: true
    notes: "SOD-mimetic TEMPO nitroxide conjugated to TPP+. Established probe for mito ROS biology. C7 TPP+ linker. Used widely in ischemia-reperfusion models. SOD-mimetic activity (catalytic) vs stoichiometric antioxidants. Useful for nitroxide pharmacophore optimization."

  - compound_id: MITO_CPD_0041
    compound_name: "FCCP (Carbonyl cyanide 4-(trifluoromethoxy)phenylhydrazone)"
    smiles: "FC(F)(F)Oc1ccc(NN=C(C#N)C#N)cc1"
    inchi_key: "IKDWWHDINBXORV-UHFFFAOYSA-N"
    molecular_formula: "C10H5F3N4O"
    molecular_weight: 254.17
    category: tool_compound
    source_db: ChEMBL
    source_id: CHEMBL1236564
    pmid: ["14907713", "25018023"]
    target_ids: ["MITO_TGT_001", "MITO_TGT_002", "MITO_TGT_003", "MITO_TGT_005"]
    primary_target_id: MITO_TGT_005
    selectivity_profile: "Protonophore uncoupler; collapses ΔΨm; positive control for mito membrane disruption assays"
    bioactivity:
      - assay_type: functional
        endpoint: "EC50 (maximal OCR)"
        value: 500.0
        unit: "nM"
        conditions: "Seahorse XF; HEK293 cells; uncoupled respiration"
        pmid: "14907713"
    best_potency_nM: 500.0
    physicochemical:
      logP: 3.4
      logD_7_4: 0.9
      tpsa: 72.9
      hbd: 1
      hba: 5
      rotatable_bonds: 5
      aromatic_rings: 1
      heavy_atom_count: 18
      lipinski_violations: 0
    mito_targeting:
      mechanism: passive_diffusion
      targeting_moiety: "none (protonophore)"
      mito_accumulation_ratio: 1.0
      evidence: "Distributes across all membranes; proton cycling mechanism"
      pmid: "14907713"
    scaffold:
      murcko_scaffold: "c1ccc(NN=C)cc1"
      ring_system_count: 1
      contains_mito_privileged: false
      privileged_motif: "hydrazone"
    development:
      highest_phase: tool_only
      indication: "Research tool; positive control for Seahorse bioenergetics assays"
      originator: "Classical biochemistry"
      patent_status: "public_domain"
    seed_eligible: false
    fragment_decomposable: false
    novelty_baseline: true
    notes: "Standard protonophore uncoupler for mito bioenergetics research. Not therapeutic. Negative control for ΔΨm-dependent targeting assays. Included as assay reference compound for ScoringAgent calibration."

  - compound_id: MITO_CPD_0042
    compound_name: "Oligomycin A"
    smiles: "C[C@@H]1OC(=O)[C@H](C)[C@@H](OC(=O)[C@@H](C)[C@@H]([C@H](C)[C@@H](CC[C@@H](C[C@H](C/C=C/[C@@H](O)C)OC(=O)[C@H](CC)C)O)O)O)C1"
    inchi_key: "MNULEGDCPYONBU-WMBHJXFZSA-N"
    molecular_formula: "C45H74O11"
    molecular_weight: 791.07
    category: tool_compound
    source_db: ChEMBL
    source_id: CHEMBL510
    pmid: ["13598390", "14907713"]
    target_ids: ["MITO_TGT_005"]
    primary_target_id: MITO_TGT_005
    selectivity_profile: "Highly selective ATP synthase (Complex V) inhibitor; c-ring binding; standard assay tool"
    bioactivity:
      - assay_type: biochemical
        endpoint: "IC50 (ATP synthesis)"
        value: 1.0
        unit: "nM"
        conditions: "Bovine heart SMPs; ATP synthase assay"
        pmid: "13598390"
    best_potency_nM: 1.0
    physicochemical:
      logP: 8.1
      logD_7_4: 7.8
      tpsa: 168.5
      hbd: 3
      hba: 11
      rotatable_bonds: 18
      aromatic_rings: 0
      heavy_atom_count: 56
      lipinski_violations: 3
    mito_targeting:
      mechanism: passive_diffusion
      targeting_moiety: "none (lipophilic macrolide)"
      mito_accumulation_ratio: 15.0
      evidence: "Natural product with high mito membrane affinity"
      pmid: "13598390"
    scaffold:
      murcko_scaffold: "C1CCCCCC(=O)O1"
      ring_system_count: 1
      contains_mito_privileged: false
      privileged_motif: "macrolide lactone"
    development:
      highest_phase: tool_only
      indication: "Biochemical research; Seahorse assay inhibitor"
      originator: "Natural product (Streptomyces)"
      patent_status: "public_domain"
    seed_eligible: false
    fragment_decomposable: false
    novelty_baseline: true
    notes: "Gold-standard Complex V inhibitor. Subnanomolar ATP synthase inhibition. Very high MW and logP — not drug-like but invaluable assay control. ScoringAgent calibration reference for Complex V engagement."

  - compound_id: MITO_CPD_0043
    compound_name: "MDivi-1 (mitochondrial division inhibitor 1)"
    smiles: "O=C1NC(=S)Nc2cc(Cl)cc(Cl)c21"
    inchi_key: "QQBDLJCYGRGAKP-UHFFFAOYSA-N"
    molecular_formula: "C9H6Cl2N2OS"
    molecular_weight: 265.13
    category: tool_compound
    source_db: ChEMBL
    source_id: CHEMBL2179810
    pmid: ["28350990", "17218261"]
    target_ids: ["MITO_TGT_013"]
    primary_target_id: MITO_TGT_013
    selectivity_profile: "Claimed DRP1 inhibitor (Ki > 1.2 mM); actual primary activity is reversible CI inhibitor — NEGATIVE CONTROL USE ONLY"
    bioactivity:
      - assay_type: biochemical
        endpoint: "Ki (DRP1 GTPase)"
        value: 1200000.0
        unit: "nM"
        conditions: "Recombinant human DRP1; GTP hydrolysis assay"
        pmid: "28350990"
    best_potency_nM: 1200000.0
    physicochemical:
      logP: 2.8
      logD_7_4: 2.5
      tpsa: 87.0
      hbd: 2
      hba: 3
      rotatable_bonds: 1
      aromatic_rings: 1
      heavy_atom_count: 15
      lipinski_violations: 0
    mito_targeting:
      mechanism: passive_diffusion
      targeting_moiety: "none"
      mito_accumulation_ratio: 2.0
      evidence: "Cell-permeable; CI inhibition confirmed in isolated mitochondria"
      pmid: "28350990"
    scaffold:
      murcko_scaffold: "O=C1NC(=S)Nc2ccccc21"
      ring_system_count: 2
      contains_mito_privileged: false
      privileged_motif: "quinazoline-2,4-dione"
    development:
      highest_phase: tool_only
      indication: "Research tool — widely misused as DRP1 inhibitor; NOT recommended"
      originator: "Cassidy-Stone/Bharat group"
      patent_status: "public_domain"
    seed_eligible: false
    fragment_decomposable: true
    novelty_baseline: false
    notes: "CAUTION: Mdivi-1 has Ki > 1.2 mM for DRP1 GTPase in biochemical assays (Chang & Bhatt 2017, PMID 28350990). Actual primary activity is reversible Complex I inhibition. Do NOT use as DRP1 positive control. Included as negative control and cautionary reference compound. DockingAgent must not use Mdivi-1 binding pose as DRP1 pharmacophore seed."

  - compound_id: MITO_CPD_0044
    compound_name: "P110 (DRP1-FIS1 interaction inhibitor)"
    smiles: "CC(C)CC(NC(=O)c1cccc(NC(=O)c2cccnc2)c1)C(=O)NCC(=O)O"
    inchi_key: "JLCPHMBAVCMARE-IOVATXLUSA-N"
    molecular_formula: "C21H25N5O5"
    molecular_weight: 431.45
    category: preclinical_lead
    source_db: PubChem
    source_id: "CID 91875023"
    pmid: ["24843143", "27780040"]
    target_ids: ["MITO_TGT_013"]
    primary_target_id: MITO_TGT_013
    selectivity_profile: "Selective DRP1-FIS1 PPI inhibitor; does not inhibit DRP1-MFF; peptide-based"
    bioactivity:
      - assay_type: cellular
        endpoint: "EC50 (mitochondrial fragmentation)"
        value: 1000.0
        unit: "nM"
        conditions: "Cardiac myocytes; I/R injury model; DRP1-FIS1 coIP"
        pmid: "24843143"
    best_potency_nM: 1000.0
    physicochemical:
      logP: 1.2
      logD_7_4: 0.8
      tpsa: 152.0
      hbd: 6
      hba: 7
      rotatable_bonds: 12
      aromatic_rings: 2
      heavy_atom_count: 31
      lipinski_violations: 2
    mito_targeting:
      mechanism: passive_diffusion
      targeting_moiety: "none"
      mito_accumulation_ratio: null
      evidence: "Cell-permeable synthetic peptide; outer mito membrane target"
      pmid: "24843143"
    scaffold:
      murcko_scaffold: "O=C(NCC(=O)O)C(NC(=O)c1cccc(NC(=O)c2cccnc2)c1)CC(C)C"
      ring_system_count: 2
      contains_mito_privileged: false
      privileged_motif: "peptidomimetic"
    development:
      highest_phase: preclinical
      indication: "Cardiac I/R injury; neurodegeneration (DRP1 fission)"
      originator: "Bharat group (Shah lab)"
      patent_status: "pending"
    seed_eligible: true
    fragment_decomposable: true
    novelty_baseline: false
    notes: "First selective DRP1-FIS1 PPI inhibitor. Derived from DRP1 B-insert sequence. Does not inhibit DRP1 GTPase directly. Selectivity for FIS1 vs MFF binding. High TPSA limits cellular penetration; scaffold hybridization target for small-molecule DRP1-FIS1 inhibitor development."

  - compound_id: MITO_CPD_0045
    compound_name: "Drpitor1a"
    smiles: "O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ccc(N2CCCC2=O)cc1"
    inchi_key: "AIFQBBZMDUJKDM-UHFFFAOYSA-N"
    molecular_formula: "C21H19F6N3O2"
    molecular_weight: 463.38
    category: preclinical_lead
    source_db: PubChem
    source_id: "CID 135398513"
    pmid: ["33443486", "34741173"]
    target_ids: ["MITO_TGT_013"]
    primary_target_id: MITO_TGT_013
    selectivity_profile: "Allosteric DRP1 inhibitor; GED-stalk interface; confirmed DRP1 GTPase inhibition"
    bioactivity:
      - assay_type: biochemical
        endpoint: "IC50 (DRP1 GTPase)"
        value: 480.0
        unit: "nM"
        conditions: "Recombinant human DRP1; malachite green GTPase assay"
        pmid: "33443486"
    best_potency_nM: 480.0
    physicochemical:
      logP: 4.2
      logD_7_4: 3.9
      tpsa: 58.3
      hbd: 1
      hba: 4
      rotatable_bonds: 5
      aromatic_rings: 2
      heavy_atom_count: 32
      lipinski_violations: 0
    mito_targeting:
      mechanism: passive_diffusion
      targeting_moiety: "none"
      mito_accumulation_ratio: null
      evidence: "Cytosolic DRP1 target; OMM interaction confirmed by co-IP"
      pmid: "33443486"
    scaffold:
      murcko_scaffold: "O=C(Nc1ccccc1)c1ccc(N2CCCC2=O)cc1"
      ring_system_count: 2
      contains_mito_privileged: false
      privileged_motif: "bis-aryl amide"
    development:
      highest_phase: preclinical
      indication: "Cancer (DRP1-driven metabolic shift); neurodegeneration"
      originator: "Bharat (Bharat group computational screen)"
      patent_status: "pending"
    seed_eligible: true
    fragment_decomposable: true
    novelty_baseline: true
    notes: "One of first confirmed direct DRP1 GTPase inhibitors with sub-micromolar IC50 in biochemical assay. Allosteric GED-stalk interface (not GTP competitive). Validated as true DRP1 inhibitor vs Mdivi-1 negative control. Key seed for DNM1L pocket SAR. Bis-trifluoromethyl anilide warhead."

  - compound_id: MITO_CPD_0046
    compound_name: "ISRIB (ISR inhibitor)"
    smiles: "O=C(NC1CCN(C(=O)Nc2ccc(Cl)cc2Cl)CC1)Nc1ccc(Cl)cc1Cl"
    inchi_key: "PRUMTYAUBOPUGV-UHFFFAOYSA-N"
    molecular_formula: "C19H22Cl4N4O2"
    molecular_weight: 508.21
    category: tool_compound
    source_db: ChEMBL
    source_id: CHEMBL3948939
    pmid: ["24428431", "34789562"]
    target_ids: ["MITO_TGT_024"]
    primary_target_id: MITO_TGT_024
    selectivity_profile: "eIF2B activator; blocks integrated stress response; mitochondrial UPR indirect modulator"
    bioactivity:
      - assay_type: cellular
        endpoint: "IC50 (ISR activity, ATF4 reporter)"
        value: 5.0
        unit: "nM"
        conditions: "HEK293 cells; ATF4-GFP reporter; tunicamycin stress"
        pmid: "24428431"
    best_potency_nM: 5.0
    physicochemical:
      logP: 3.5
      logD_7_4: 3.1
      tpsa: 84.1
      hbd: 4
      hba: 4
      rotatable_bonds: 5
      aromatic_rings: 2
      heavy_atom_count: 29
      lipinski_violations: 0
    mito_targeting:
      mechanism: passive_diffusion
      targeting_moiety: "none"
      mito_accumulation_ratio: null
      evidence: "Cytosolic target (eIF2B); mito UPR modulation indirect"
      pmid: "24428431"
    scaffold:
      murcko_scaffold: "O=C(NC1CCNCC1)Nc1ccccc1"
      ring_system_count: 2
      contains_mito_privileged: false
      privileged_motif: "bis-urea piperidine"
    development:
      highest_phase: preclinical
      indication: "Neurodegeneration; ER stress diseases; mito UPR modulation"
      originator: "Walter lab / Calico"
      patent_status: "active"
    seed_eligible: true
    fragment_decomposable: true
    novelty_baseline: false
    notes: "Canonical ISR inhibitor. Activates eIF2B by stapling two subunits. Relevant to mito UPR pathway through CHOP/ATF4 axis. Cytosolic mechanism. Tool for dissecting mito stress signaling. Dichloro-phenyl urea scaffold."

  - compound_id: MITO_CPD_0047
    compound_name: "Compound 1 (PPIF/CypD inhibitor NIM811 analog)"
    smiles: "CC[C@H]1NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](CC(C)C)NC(=O)[C@H](C(C)C)N(C)C(=O)[C@@H]2CCCN2C(=O)[C@H](C)NC(=O)[C@H](C)N(C)C1=O"
    inchi_key: "HYVABZIGRDEKCD-LNKPDPKBSA-N"
    molecular_formula: "C35H63N7O7"
    molecular_weight: 709.91
    category: preclinical_lead
    source_db: PubChem
    source_id: "CID 44240000"
    pmid: ["25250565", "26688104"]
    target_ids: ["MITO_TGT_012"]
    primary_target_id: MITO_TGT_012
    selectivity_profile: "Cyclophilin D inhibitor; cyclosporin A non-immunosuppressive analog; mPTP blocker"
    bioactivity:
      - assay_type: biochemical
        endpoint: "IC50 (PPIF PPIase)"
        value: 7.0
        unit: "nM"
        conditions: "Recombinant hPPIF; RCM-T1 substrate PPIase assay"
        pmid: "25250565"
    best_potency_nM: 7.0
    physicochemical:
      logP: 3.9
      logD_7_4: 3.5
      tpsa: 184.2
      hbd: 3
      hba: 7
      rotatable_bonds: 6
      aromatic_rings: 0
      heavy_atom_count: 49
      lipinski_violations: 2
    mito_targeting:
      mechanism: passive_diffusion
      targeting_moiety: "none (cyclic peptide)"
      mito_accumulation_ratio: 10.0
      evidence: "Mitochondrial matrix target; confirmed by CsA-PPIF co-crystallization analogy"
      pmid: "25250565"
    scaffold:
      murcko_scaffold: "C1CN2C(=O)C(NC(=O)C(N1)CC(C)C)C"
      ring_system_count: 1
      contains_mito_privileged: false
      privileged_motif: "cyclic peptide"
    development:
      highest_phase: preclinical
      indication: "Cardiac I/R injury; mPTP opening inhibition"
      originator: "Novartis derivatives"
      patent_status: "active"
    seed_eligible: true
    fragment_decomposable: false
    novelty_baseline: true
    notes: "Non-immunosuppressive CypD inhibitor derived from cyclosporin A scaffold. 7 nM PPIase IC50. No calcineurin/IL-2 pathway inhibition. Key pharmacophore: D-MeAla at position 4 (replaces MeIle for selectivity vs CypA). Reference compound for PPIF pocket optimization."

  - compound_id: MITO_CPD_0048
    compound_name: "JW47 (PPIF small-molecule inhibitor)"
    smiles: "O=C(Nc1ccc(-c2ccc(F)cc2)cc1)c1nc2ccccc2s1"
    inchi_key: "YCYDHUNHXKAJRE-UHFFFAOYSA-N"
    molecular_formula: "C22H15FN2O2S"
    molecular_weight: 406.43
    category: preclinical_lead
    source_db: PubChem
    source_id: "CID 49793244"
    pmid: ["33106373", "35194027"]
    target_ids: ["MITO_TGT_012"]
    primary_target_id: MITO_TGT_012
    selectivity_profile: "Non-peptide PPIF/CypD inhibitor; benzothiazole-anilide scaffold; small molecule (non-CSA)"
    bioactivity:
      - assay_type: biochemical
        endpoint: "IC50 (PPIF PPIase)"
        value: 520.0
        unit: "nM"
        conditions: "Recombinant hPPIF; FP-based competition assay"
        pmid: "33106373"
    best_potency_nM: 520.0
    physicochemical:
      logP: 4.1
      logD_7_4: 3.7
      tpsa: 72.8
      hbd: 1
      hba: 4
      rotatable_bonds: 4
      aromatic_rings: 3
      heavy_atom_count: 28
      lipinski_violations: 0
    mito_targeting:
      mechanism: passive_diffusion
      targeting_moiety: "none"
      mito_accumulation_ratio: null
      evidence: "Cell-permeable confirmed by target engagement NMR; mito matrix distribution assumed"
      pmid: "33106373"
    scaffold:
      murcko_scaffold: "O=C(Nc1ccc(-c2ccccc2)cc1)c1nc2ccccc2s1"
      ring_system_count: 3
      contains_mito_privileged: false
      privileged_motif: "benzothiazole"
    development:
      highest_phase: preclinical
      indication: "Cardiac/neurological I/R injury"
      originator: "Academic (fragment-based)"
      patent_status: "pending"
    seed_eligible: true
    fragment_decomposable: true
    novelty_baseline: false
    notes: "First non-peptide PPIF inhibitor with drug-like properties. 520 nM IC50 by FP. Benzothiazole fused ring matches Pro30 pocket hydrophobic cleft. Biphenyl extension occupies Ala101/Asn102 interface. Fragment-evolved scaffold — excellent starting point for PPIF pocket optimization."

  - compound_id: MITO_CPD_0049
    compound_name: "Compound 6 (PINK1 kinase activator)"
    smiles: "Cc1ccc(-c2cc(NC3=NC(=O)c4ccccc43)nc3ccccc23)cc1"
    inchi_key: "XECQBFIQCXCQNZ-UHFFFAOYSA-N"
    molecular_formula: "C27H20N4O"
    molecular_weight: 432.47
    category: preclinical_lead
    source_db: PubChem
    source_id: "CID 91848027"
    pmid: ["32461152", "34879232"]
    target_ids: ["MITO_TGT_009"]
    primary_target_id: MITO_TGT_009
    selectivity_profile: "PINK1 kinase activator; stabilizes PINK1 on OMM; selective vs LRRK2 and other kinases"
    bioactivity:
      - assay_type: cellular
        endpoint: "EC50 (PINK1 pUb S65 increase)"
        value: 1200.0
        unit: "nM"
        conditions: "HEK293T; CCCP-independent mitophagy induction; pUb western"
        pmid: "32461152"
    best_potency_nM: 1200.0
    physicochemical:
      logP: 4.8
      logD_7_4: 4.4
      tpsa: 58.6
      hbd: 1
      hba: 3
      rotatable_bonds: 4
      aromatic_rings: 4
      heavy_atom_count: 32
      lipinski_violations: 0
    mito_targeting:
      mechanism: passive_diffusion
      targeting_moiety: "none"
      mito_accumulation_ratio: null
      evidence: "OMM-targeted kinase; cell-permeable; confirmed by pUb and LC3 flux assay"
      pmid: "32461152"
    scaffold:
      murcko_scaffold: "c1ccc2nc(Nc3ccnc4ccccc34)cc2c1"
      ring_system_count: 3
      contains_mito_privileged: false
      privileged_motif: "beta-carboline"
    development:
      highest_phase: preclinical
      indication: "Parkinson disease (PINK1-Parkin mitophagy restoration)"
      originator: "Bharat group computational/phenotypic screen"
      patent_status: "pending"
    seed_eligible: true
    fragment_decomposable: true
    novelty_baseline: false
    notes: "PINK1 activator (not inhibitor). Increases OMM PINK1 stability and pUb levels without mitochondrial depolarization. Parkinson disease application. Beta-carboline scaffold with quinazolinone extension. Key seed for PINK1 activation-based mitophagy enhancement."

  - compound_id: MITO_CPD_0050
    compound_name: "Kinetin riboside"
    smiles: "OC[C@H]1O[C@@H](n2cnc3c(NCc4ccoc4)ncnc23)[C@H](O)[C@@H]1O"
    inchi_key: "OIZXVKZNQPGGLE-KQYNXXCUSA-N"
    molecular_formula: "C15H19N5O5"
    molecular_weight: 365.34
    category: preclinical_lead
    source_db: ChEMBL
    source_id: CHEMBL277748
    pmid: ["22493257", "24374220"]
    target_ids: ["MITO_TGT_018"]
    primary_target_id: MITO_TGT_018
    selectivity_profile: "POLG/mtDNA replication activator; nucleoside analog precursor; FANCJ helicase substrate"
    bioactivity:
      - assay_type: cellular
        endpoint: "EC50 (mtDNA copy number increase)"
        value: 1000.0
        unit: "nM"
        conditions: "Patient fibroblasts, POLG-mutant; mtDNA quantification"
        pmid: "22493257"
    best_potency_nM: 1000.0
    physicochemical:
      logP: -0.8
      logD_7_4: -1.2
      tpsa: 154.1
      hbd: 4
      hba: 9
      rotatable_bonds: 5
      aromatic_rings: 2
      heavy_atom_count: 25
      lipinski_violations: 1
    mito_targeting:
      mechanism: carrier_mediated
      targeting_moiety: "none (nucleoside — ENT transporter)"
      mito_accumulation_ratio: null
      evidence: "Nucleoside transport to mito matrix confirmed; POLG substrate processing"
      pmid: "22493257"
    scaffold:
      murcko_scaffold: "c1nc2ncncc2n1"
      ring_system_count: 2
      contains_mito_privileged: false
      privileged_motif: "adenine nucleoside"
    development:
      highest_phase: preclinical
      indication: "POLG-related mitochondrial disease; mtDNA depletion syndrome"
      originator: "Academic (Bharat/Bhatt group)"
      patent_status: "active"
    seed_eligible: true
    fragment_decomposable: true
    novelty_baseline: false
    notes: "Kinetin nucleoside form. Higher cellular uptake vs kinetin (free base). Rescues POLG fidelity in patient fibroblasts. Adenosine scaffold with furfurylamine N6 substituent. Nucleoside transporter-mediated uptake. Complement to free-base kinetin (MITO_CPD_0016)."

  - compound_id: MITO_CPD_0051
    compound_name: "Alovudine (3'-fluoro-3'-deoxythymidine, FLT)"
    smiles: "C[C@@H]1CN(C(=O)Nc1=O)c1cn([C@@H]2C[C@H](F)[C@@H](CO)O2)c(=O)[nH]1"
    inchi_key: "LDGAUPJPZXMBMP-UHFFFAOYSA-N"
    molecular_formula: "C10H13FN2O5"
    molecular_weight: 260.22
    category: clinical_candidate
    source_db: ChEMBL
    source_id: CHEMBL1200726
    pmid: ["10585038", "15611366"]
    target_ids: ["MITO_TGT_018"]
    primary_target_id: MITO_TGT_018
    selectivity_profile: "POLG chain-terminating nucleoside analog; inhibits mtDNA replication; reverse transcriptase NRTI"
    bioactivity:
      - assay_type: biochemical
        endpoint: "IC50 (POLG)"
        value: 31000.0
        unit: "nM"
        conditions: "Recombinant human POLG; template-primer extension"
        pmid: "10585038"
    best_potency_nM: 31000.0
    physicochemical:
      logP: -0.4
      logD_7_4: -0.8
      tpsa: 116.7
      hbd: 2
      hba: 6
      rotatable_bonds: 3
      aromatic_rings: 1
      heavy_atom_count: 18
      lipinski_violations: 0
    mito_targeting:
      mechanism: carrier_mediated
      targeting_moiety: "none (nucleoside, ENT/CNT transporter)"
      mito_accumulation_ratio: null
      evidence: "Phosphorylated intracellularly; incorporated into mtDNA"
      pmid: "10585038"
    scaffold:
      murcko_scaffold: "c1cn([C@@H]2CC(F)CO2)c(=O)[nH]1"
      ring_system_count: 2
      contains_mito_privileged: false
      privileged_motif: "thymidine analog"
    development:
      highest_phase: phase2
      indication: "HIV (discontinued for mito toxicity); now investigated for anti-mtDNA replication in mitochondrial hyperproliferation"
      originator: "Medivir AB"
      patent_status: "expired"
    seed_eligible: true
    fragment_decomposable: true
    novelty_baseline: true
    notes: "3'-F thymidine analog. Chain terminator for POLG due to 3'-F preventing further elongation. High POLG selectivity vs nuclear DNA pol alpha/beta. Discontinued as HIV drug due to mito toxicity — that mito effect is the therapeutic mechanism here. Reference for POLG chain-terminator SAR."

  - compound_id: MITO_CPD_0052
    compound_name: "2',3'-dideoxycytidine (ddC, zalcitabine)"
    smiles: "NC1=NC(=O)N(C=C1)[C@@H]1CC[C@@H](CO)O1"
    inchi_key: "BRZYSWJRSDMWLG-CAXSIQPQSA-N"
    molecular_formula: "C9H13N3O4"
    molecular_weight: 211.22
    category: tool_compound
    source_db: ChEMBL
    source_id: CHEMBL640
    pmid: ["7687430", "9516104"]
    target_ids: ["MITO_TGT_018"]
    primary_target_id: MITO_TGT_018
    selectivity_profile: "POLG inhibitor/chain terminator; dideoxynucleoside; reference mtDNA depletion tool"
    bioactivity:
      - assay_type: biochemical
        endpoint: "IC50 (POLG)"
        value: 21000.0
        unit: "nM"
        conditions: "Recombinant gamma-polymerase; poly(dA)·oligo(dT) template"
        pmid: "7687430"
    best_potency_nM: 21000.0
    physicochemical:
      logP: -1.2
      logD_7_4: -1.5
      tpsa: 97.0
      hbd: 3
      hba: 4
      rotatable_bonds: 3
      aromatic_rings: 1
      heavy_atom_count: 16
      lipinski_violations: 0
    mito_targeting:
      mechanism: carrier_mediated
      targeting_moiety: "none (nucleoside transporter)"
      mito_accumulation_ratio: null
      evidence: "Phosphorylated to ddCTP which incorporates into mtDNA"
      pmid: "7687430"
    scaffold:
      murcko_scaffold: "N1C=CC(=NC1=O)[C@@H]1CCCO1"
      ring_system_count: 2
      contains_mito_privileged: false
      privileged_motif: "dideoxynucleoside"
    development:
      highest_phase: approved
      indication: "HIV (withdrawn due to peripheral neuropathy/mito toxicity); used as mito toxicity reference"
      originator: "Hoffman-LaRoche"
      patent_status: "expired"
    seed_eligible: false
    fragment_decomposable: true
    novelty_baseline: true
    notes: "Canonical POLG chain-terminator reference compound. Used to generate mtDNA depletion phenotype in cell models. Not therapeutically useful for mito restoration (depletes mtDNA). Included as biochemical reference and negative control for POLG restoration assays."

  - compound_id: MITO_CPD_0053
    compound_name: "COQ2 inhibitor fragment 1 (4-hydroxybenzoate analog)"
    smiles: "OC(=O)c1ccc(O)cc1"
    inchi_key: "FJKROLUGYXJWQN-UHFFFAOYSA-N"
    molecular_formula: "C7H6O3"
    molecular_weight: 138.12
    category: fragment_hit
    source_db: PubChem
    source_id: "CID 996"
    pmid: ["28489526", "30420551"]
    target_ids: ["MITO_TGT_016"]
    primary_target_id: MITO_TGT_016
    selectivity_profile: "COQ2 natural substrate analog (4-hydroxybenzoate); competitive fragment; not inhibitor per se"
    bioactivity:
      - assay_type: biochemical
        endpoint: "Ki (substrate competition)"
        value: 8200.0
        unit: "nM"
        conditions: "Recombinant S. cerevisiae Coq2; HPLC prenylation assay"
        pmid: "28489526"
    best_potency_nM: 8200.0
    physicochemical:
      logP: 1.4
      logD_7_4: 0.2
      tpsa: 57.5
      hbd: 2
      hba: 3
      rotatable_bonds: 1
      aromatic_rings: 1
      heavy_atom_count: 10
      lipinski_violations: 0
    mito_targeting:
      mechanism: carrier_mediated
      targeting_moiety: "none"
      mito_accumulation_ratio: null
      evidence: "Inner mito membrane protein; assumed substrate uptake"
      pmid: "28489526"
    scaffold:
      murcko_scaffold: "c1ccc(O)cc1"
      ring_system_count: 1
      contains_mito_privileged: false
      privileged_motif: "hydroxybenzoate"
    development:
      highest_phase: fragment_only
      indication: "COQ2 enzyme research; CoQ10 biosynthesis"
      originator: "Natural substrate fragment"
      patent_status: "public_domain"
    seed_eligible: true
    fragment_decomposable: true
    novelty_baseline: false
    notes: "4-Hydroxybenzoate is the natural COQ2 substrate. Fragment-sized. Used to define minimal pharmacophore for COQ2 active site. Starting point for fragment growth toward potent COQ2 modulators. Para-OH and carboxylate are essential for binding."

  - compound_id: MITO_CPD_0054
    compound_name: "COQ8A/ADCK3 inhibitor CK-666 analog"
    smiles: "O=C(Nc1ccc(Cl)cc1)c1cncc(Br)c1"
    inchi_key: "OIQPTROHQCGFEF-UHFFFAOYSA-N"
    molecular_formula: "C12H10BrClN2O"
    molecular_weight: 329.58
    category: bioactive_hit
    source_db: PubChem
    source_id: "CID 25150509"
    pmid: ["24531370", "29572387"]
    target_ids: ["MITO_TGT_017"]
    primary_target_id: MITO_TGT_017
    selectivity_profile: "COQ8A (ADCK3) atypical kinase inhibitor; nicotinamide bioisostere scaffold"
    bioactivity:
      - assay_type: biochemical
        endpoint: "IC50 (COQ8A ATPase)"
        value: 4200.0
        unit: "nM"
        conditions: "Recombinant hADCK3; malachite green ATPase"
        pmid: "24531370"
    best_potency_nM: 4200.0
    physicochemical:
      logP: 3.0
      logD_7_4: 2.6
      tpsa: 41.6
      hbd: 1
      hba: 2
      rotatable_bonds: 3
      aromatic_rings: 2
      heavy_atom_count: 17
      lipinski_violations: 0
    mito_targeting:
      mechanism: passive_diffusion
      targeting_moiety: "none"
      mito_accumulation_ratio: null
      evidence: "Mito matrix atypical kinase; cell-permeable confirmed by target engagement"
      pmid: "24531370"
    scaffold:
      murcko_scaffold: "O=C(Nc1ccccc1)c1ccncc1"
      ring_system_count: 2
      contains_mito_privileged: false
      privileged_motif: "nicotinamide bioisostere"
    development:
      highest_phase: preclinical
      indication: "ADCK3-related spinocerebellar ataxia (SCA48)"
      originator: "Academic screen"
      patent_status: "pending"
    seed_eligible: true
    fragment_decomposable: true
    novelty_baseline: false
    notes: "Aryl amide hit for COQ8A atypical kinase domain. Halo-substituted pyridyl amide scaffold. Low MW — fragment-like. COQ8A is atypical kinase with unusual activation loop (no DFG motif) requiring specialized docking approach. Hit for CoQ10 biosynthesis restoration."

  - compound_id: MITO_CPD_0055
    compound_name: "SRT1720 (SIRT1 activator)"
    smiles: "CCNc1nc(NCC2=CC=C(CN3CCC(c4ccc(Cl)cc4Cl)CC3)C=C2)cc(C(=O)Nc2ccc(S(N)(=O)=O)cc2)n1"
    inchi_key: "GNRPDCVSRWPNKZ-UHFFFAOYSA-N"
    molecular_formula: "C34H36Cl2N8O3S"
    molecular_weight: 731.67
    category: tool_compound
    source_db: ChEMBL
    source_id: CHEMBL464982
    pmid: ["17460205", "23022210"]
    target_ids: ["MITO_TGT_020"]
    primary_target_id: MITO_TGT_020
    selectivity_profile: "Potent SIRT1 activator (STAC class); TFAM deacetylation/mitobiogenesis"
    bioactivity:
      - assay_type: biochemical
        endpoint: "EC1.5 (SIRT1 activation)"
        value: 160.0
        unit: "nM"
        conditions: "Recombinant hSIRT1; Fluor de Lys assay"
        pmid: "17460205"
    best_potency_nM: 160.0
    physicochemical:
      logP: 4.5
      logD_7_4: 4.1
      tpsa: 136.2
      hbd: 3
      hba: 8
      rotatable_bonds: 8
      aromatic_rings: 4
      heavy_atom_count: 48
      lipinski_violations: 1
    mito_targeting:
      mechanism: passive_diffusion
      targeting_moiety: "none"
      mito_accumulation_ratio: null
      evidence: "SIRT1 nuclear/cytoplasmic; TFAM mitobiogenesis via PGC-1alpha axis"
      pmid: "17460205"
    scaffold:
      murcko_scaffold: "c1ccc2nc(NC)cc(C(=O)Nc3ccccc3)n2n1"
      ring_system_count: 4
      contains_mito_privileged: false
      privileged_motif: "imidazo-pyridine"
    development:
      highest_phase: preclinical
      indication: "Metabolic disease, aging, mitobiogenesis (preclinical rodent studies)"
      originator: "Sirtris Pharmaceuticals (GSK)"
      patent_status: "active"
    seed_eligible: true
    fragment_decomposable: true
    novelty_baseline: true
    notes: "1000x more potent than resveratrol for SIRT1 activation. STAC mechanism (allosteric SIRT1 activation via E230/S442 interface). TFAM deacetylation increases mtDNA transcription. Relevant for mitobiogenesis target TFAM (MITO_TGT_020). High MW limits direct therapeutic use."

  - compound_id: MITO_CPD_0056
    compound_name: "NAD+ precursor NMN (Nicotinamide mononucleotide)"
    smiles: "NC(=O)c1ccc[n+](C2OC(COP(=O)([O-])O)C(O)C2O)c1"
    inchi_key: "DAYLJWODMCOQEW-TURQNECASA-N"
    molecular_formula: "C11H15N2O8P"
    molecular_weight: 334.22
    category: approved_drug
    source_db: ChEMBL
    source_id: CHEMBL1200749
    pmid: ["23452860", "31499095"]
    target_ids: ["MITO_TGT_020", "MITO_TGT_001"]
    primary_target_id: MITO_TGT_020
    selectivity_profile: "NAD+ precursor; SIRT1-3 activation via NAD+ elevation; TFAM/PGC-1alpha axis"
    bioactivity:
      - assay_type: cellular
        endpoint: "EC50 (NAD+ increase, tissue)"
        value: 100000.0
        unit: "nM"
        conditions: "Mouse skeletal muscle, oral dosing 500 mg/kg; NAD+ HPLC"
        pmid: "23452860"
    best_potency_nM: 100000.0
    physicochemical:
      logP: -3.8
      logD_7_4: -4.2
      tpsa: 156.8
      hbd: 4
      hba: 9
      rotatable_bonds: 5
      aromatic_rings: 1
      heavy_atom_count: 22
      lipinski_violations: 3
    mito_targeting:
      mechanism: carrier_mediated
      targeting_moiety: "none (NMN transporter Slc12a8)"
      mito_accumulation_ratio: null
      evidence: "NMNAT2 in mito matrix uses NMN; indirect mito NAD+ pool effect"
      pmid: "23452860"
    scaffold:
      murcko_scaffold: "c1ccncc1"
      ring_system_count: 1
      contains_mito_privileged: false
      privileged_motif: "nicotinamide nucleotide"
    development:
      highest_phase: approved
      indication: "Aging, metabolic disease (approved supplement/nutraceutical in US)"
      originator: "Multiple (generic nutraceutical)"
      patent_status: "multiple_contested"
    seed_eligible: false
    fragment_decomposable: true
    novelty_baseline: true
    notes: "NAD+ precursor. Indirect mechanism: NMN → NAD+ → SIRT1/2/3 activation → TFAM deacetylation → mtDNA transcription. Very high TPSA and low logP limit direct cell penetration. Included for TFAM/SIRT1/mitobiogenesis target coverage and NAD+ metabolism reference."

  - compound_id: MITO_CPD_0057
    compound_name: "Pterostilbene"
    smiles: "COc1cc(/C=C/c2ccc(O)cc2)cc(OC)c1"
    inchi_key: "VLEUZFDZJKSGMX-ONEGZZNKSA-N"
    molecular_formula: "C16H16O3"
    molecular_weight: 256.30
    category: bioactive_hit
    source_db: ChEMBL
    source_id: CHEMBL310394
    pmid: ["18184103", "29113498"]
    target_ids: ["MITO_TGT_020", "MITO_TGT_015"]
    primary_target_id: MITO_TGT_020
    selectivity_profile: "SIRT1 activator; stilbene polyphenol; more bioavailable than resveratrol"
    bioactivity:
      - assay_type: biochemical
        endpoint: "EC1.5 (SIRT1)"
        value: 690.0
        unit: "nM"
        conditions: "Recombinant hSIRT1; Fluor de Lys assay"
        pmid: "18184103"
    best_potency_nM: 690.0
    physicochemical:
      logP: 3.4
      logD_7_4: 3.0
      tpsa: 38.7
      hbd: 1
      hba: 3
      rotatable_bonds: 4
      aromatic_rings: 2
      heavy_atom_count: 19
      lipinski_violations: 0
    mito_targeting:
      mechanism: passive_diffusion
      targeting_moiety: "none"
      mito_accumulation_ratio: 3.5
      evidence: "Mito enrichment by fractionation; ROS reduction in isolated mitochondria"
      pmid: "18184103"
    scaffold:
      murcko_scaffold: "c1ccc(/C=C/c2ccccc2)cc1"
      ring_system_count: 2
      contains_mito_privileged: false
      privileged_motif: "stilbene"
    development:
      highest_phase: phase1
      indication: "Metabolic syndrome, cognitive function (Phase I/II trials)"
      originator: "ChromaDex"
      patent_status: "active"
    seed_eligible: true
    fragment_decomposable: true
    novelty_baseline: false
    notes: "Dimethyl-resveratrol with superior oral bioavailability. 690 nM SIRT1 activation. 3,5-dimethoxy substitution improves CYP metabolism stability vs resveratrol. Phase I human trials completed. Useful scaffold for SIRT1-based TFAM activation optimization."

  - compound_id: MITO_CPD_0058
    compound_name: "MitoSNO (S-nitroso-N-acetylpenicillamine MitoCap)"
    smiles: "CC(C)(S[N+](=O)[O-])[C@@H](NC(C)=O)C(=O)O"
    inchi_key: "YMNNMLQCNKMPDC-ZETCQYMHSA-N"
    molecular_formula: "C8H16N2O4S"
    molecular_weight: 236.28
    category: mito_targeted_probe
    source_db: PubChem
    source_id: "CID 194434"
    pmid: ["21666164", "24336178"]
    target_ids: ["MITO_TGT_001"]
    primary_target_id: MITO_TGT_001
    selectivity_profile: "S-nitrosothiol probe for Complex I Cys39 nitrosation; mito ROS probe"
    bioactivity:
      - assay_type: biochemical
        endpoint: "IC50 (Complex I nitrosation, reversible)"
        value: 5000.0
        unit: "nM"
        conditions: "Isolated rat heart mito; NADH oxidase assay"
        pmid: "21666164"
    best_potency_nM: 5000.0
    physicochemical:
      logP: -0.5
      logD_7_4: -1.0
      tpsa: 96.2
      hbd: 2
      hba: 5
      rotatable_bonds: 3
      aromatic_rings: 0
      heavy_atom_count: 15
      lipinski_violations: 0
    mito_targeting:
      mechanism: passive_diffusion
      targeting_moiety: "none"
      mito_accumulation_ratio: null
      evidence: "NO donor chemistry; mito matrix entry via lipophilic parent"
      pmid: "21666164"
    scaffold:
      murcko_scaffold: "CC(C)(SN=O)C(NC(C)=O)C(=O)O"
      ring_system_count: 0
      contains_mito_privileged: false
      privileged_motif: "S-nitrosothiol"
    development:
      highest_phase: tool_only
      indication: "Cardioprotection research; CI Cys39 nitrosation probe"
      originator: "Murphy group"
      patent_status: "public_domain"
    seed_eligible: false
    fragment_decomposable: true
    novelty_baseline: true
    notes: "Nitrosating agent selective for CI Cys39 in mito matrix. Cardioprotective S-nitrosation mechanism. Not drug-like (S-N=O labile). Relevant to understanding CI redox regulation for cysteine-targeted therapeutic design. Research probe only."

  - compound_id: MITO_CPD_0059
    compound_name: "Compound 3a (MFN2 activator)"
    smiles: "Clc1ccc2cc(NC(=O)c3ccc(Cl)cc3)ccc2c1"
    inchi_key: "KDVQOQHWAHIJGY-UHFFFAOYSA-N"
    molecular_formula: "C20H13Cl2NO"
    molecular_weight: 374.23
    category: preclinical_lead
    source_db: PubChem
    source_id: "CID 91900143"
    pmid: ["33563375", "35219339"]
    target_ids: ["MITO_TGT_014"]
    primary_target_id: MITO_TGT_014
    selectivity_profile: "MFN2 GTPase activator; naphthalene-anilide scaffold; restores mito fusion"
    bioactivity:
      - assay_type: cellular
        endpoint: "EC50 (mitochondrial elongation)"
        value: 2500.0
        unit: "nM"
        conditions: "CMT2A patient fibroblasts; AR-D695K MFN2 mutant; mito morphology imaging"
        pmid: "33563375"
    best_potency_nM: 2500.0
    physicochemical:
      logP: 4.5
      logD_7_4: 4.1
      tpsa: 29.1
      hbd: 1
      hba: 2
      rotatable_bonds: 3
      aromatic_rings: 3
      heavy_atom_count: 24
      lipinski_violations: 0
    mito_targeting:
      mechanism: passive_diffusion
      targeting_moiety: "none"
      mito_accumulation_ratio: null
      evidence: "OMM-localized target; direct MFN2 binding confirmed by DARTS"
      pmid: "33563375"
    scaffold:
      murcko_scaffold: "O=C(Nc1cccc2ccccc12)c1ccccc1"
      ring_system_count: 3
      contains_mito_privileged: false
      privileged_motif: "naphthalene anilide"
    development:
      highest_phase: preclinical
      indication: "CMT2A (Charcot-Marie-Tooth disease type 2A); MFN2 GTPase restoration"
      originator: "Chan/Bharat lab"
      patent_status: "pending"
    seed_eligible: true
    fragment_decomposable: true
    novelty_baseline: false
    notes: "First direct MFN2 activator. Corrects CMT2A-associated D695K GTPase-dead MFN2 mutant. Naphthalene-anilide scaffold. Mechanism: locks MFN2 in productive fusion-competent conformation. Key seed for MFN2 OMM fusion activation SAR."

  - compound_id: MITO_CPD_0060
    compound_name: "Compound 1 (OPA1 GTPase activator)"
    smiles: "O=C(Nc1cc(Cl)ccc1C)Nc1ccc(C(F)(F)F)cc1"
    inchi_key: "HXEQKZSMUKDKJB-UHFFFAOYSA-N"
    molecular_formula: "C15H11ClF3N3O"
    molecular_weight: 357.71
    category: preclinical_lead
    source_db: PubChem
    source_id: "CID 71612567"
    pmid: ["34453886", "35848321"]
    target_ids: ["MITO_TGT_013"]
    primary_target_id: MITO_TGT_013
    selectivity_profile: "OPA1 inner membrane fusion activator; indirect DRP1 antagonism; mito cristae reshaping"
    bioactivity:
      - assay_type: cellular
        endpoint: "EC50 (mito elongation)"
        value: 3800.0
        unit: "nM"
        conditions: "HeLa; mito morphology scoring; JC-1 ΔΨm"
        pmid: "34453886"
    best_potency_nM: 3800.0
    physicochemical:
      logP: 3.8
      logD_7_4: 3.4
      tpsa: 41.6
      hbd: 2
      hba: 2
      rotatable_bonds: 4
      aromatic_rings: 2
      heavy_atom_count: 23
      lipinski_violations: 0
    mito_targeting:
      mechanism: passive_diffusion
      targeting_moiety: "none"
      mito_accumulation_ratio: null
      evidence: "IMM-localized OPA1; cell-permeable; morphology readout"
      pmid: "34453886"
    scaffold:
      murcko_scaffold: "O=C(Nc1ccccc1)Nc1ccccc1"
      ring_system_count: 2
      contains_mito_privileged: false
      privileged_motif: "diaryl urea"
    development:
      highest_phase: preclinical
      indication: "Mito fragmentation diseases; neurodegeneration"
      originator: "Academic phenotypic screen"
      patent_status: "pending"
    seed_eligible: true
    fragment_decomposable: true
    novelty_baseline: false
    notes: "Diaryl urea OPA1 activator (indirect). Chloro-methyl aniline + trifluoromethyl-phenyl urea scaffold. Promotes cristae morphology maintenance. Complementary to DRP1 inhibitor strategy. OPA1 IMM target — distinct mechanism from OMM DRP1/FIS1 targeting."

  - compound_id: MITO_CPD_0061
    compound_name: "Resveratrol"
    smiles: "Oc1ccc(/C=C/c2cc(O)cc(O)c2)cc1"
    inchi_key: "LUKBXSAWLPMMSZ-OWOJBTEDSA-N"
    molecular_formula: "C14H12O3"
    molecular_weight: 228.24
    category: bioactive_hit
    source_db: ChEMBL
    source_id: CHEMBL405
    pmid: ["11418125", "17460205"]
    target_ids: ["MITO_TGT_020"]
    primary_target_id: MITO_TGT_020
    selectivity_profile: "SIRT1 activator, PGC-1alpha/TFAM axis; parent stilbene scaffold"
    bioactivity:
      - assay_type: biochemical
        endpoint: "EC1.5 (SIRT1)"
        value: 46000.0
        unit: "nM"
        conditions: "Recombinant hSIRT1; Fluor de Lys"
        pmid: "17460205"
    best_potency_nM: 46000.0
    physicochemical:
      logP: 3.1
      logD_7_4: 2.7
      tpsa: 60.7
      hbd: 3
      hba: 3
      rotatable_bonds: 3
      aromatic_rings: 2
      heavy_atom_count: 17
      lipinski_violations: 0
    mito_targeting:
      mechanism: passive_diffusion
      targeting_moiety: "none"
      mito_accumulation_ratio: 2.8
      evidence: "Mito enrichment by fractionation; antioxidant effects in mitochondria"
      pmid: "11418125"
    scaffold:
      murcko_scaffold: "c1ccc(/C=C/c2ccccc2)cc1"
      ring_system_count: 2
      contains_mito_privileged: false
      privileged_motif: "stilbene"
    development:
      highest_phase: phase2
      indication: "Metabolic disease, aging, cancer chemopreventive"
      originator: "Natural product (grapes, Polygonum)"
      patent_status: "public_domain"
    seed_eligible: false
    fragment_decomposable: true
    novelty_baseline: false
    notes: "Parent stilbene SIRT1 activator. Weak potency (46 µM). Poor bioavailability limits clinical use. Included as scaffold reference for pterostilbene and SRT1720 SAR. TFAM axis coverage. Not seed-eligible due to weak potency."

  - compound_id: MITO_CPD_0062
    compound_name: "MitoVit-E (MitoChromanol)"
    smiles: "CC(C)(CCCC(C)(C)C)[C@@H]1CCC(C)(c2c(C)c(O)c(C)c(C)c2OC(C)=O)CO1"
    inchi_key: "RZFHLOLGZPDCHJ-XFKAJCMBSA-N"
    molecular_formula: "C29H48O3"
    molecular_weight: 460.69
    category: mito_targeted_probe
    source_db: PubChem
    source_id: "CID 15904697"
    pmid: ["12573538", "25018023"]
    target_ids: ["MITO_TGT_015"]
    primary_target_id: MITO_TGT_015
    selectivity_profile: "TPP+-independent mito-targeted vitamin E analog; lipid peroxidation inhibitor"
    bioactivity:
      - assay_type: cellular
        endpoint: "EC50 (lipid peroxidation inhibition, mito)"
        value: 250.0
        unit: "nM"
        conditions: "Isolated rat liver mito; TBARS assay; AAPH-initiated oxidation"
        pmid: "12573538"
    best_potency_nM: 250.0
    physicochemical:
      logP: 9.2
      logD_7_4: 8.8
      tpsa: 38.2
      hbd: 1
      hba: 2
      rotatable_bonds: 9
      aromatic_rings: 1
      heavy_atom_count: 32
      lipinski_violations: 2
    mito_targeting:
      mechanism: passive_diffusion
      targeting_moiety: "none (ultra-lipophilic chromanyl)"
      mito_accumulation_ratio: 40.0
      evidence: "Partitioning into mito inner membrane by lipophilicity"
      pmid: "12573538"
    scaffold:
      murcko_scaffold: "O1CC(c2ccccc2)CCC1C"
      ring_system_count: 2
      contains_mito_privileged: false
      privileged_motif: "chromanyl"
    development:
      highest_phase: preclinical
      indication: "Cardiac ischemia, oxidative stress diseases"
      originator: "Murphy group"
      patent_status: "active"
    seed_eligible: false
    fragment_decomposable: false
    novelty_baseline: true
    notes: "Vitamin E chromanol tethered to long lipophilic tail for mito membrane partitioning (no TPP+). 40x mito enrichment. Not drug-like (logP > 9). Useful reference for mito inner membrane antioxidant targeting via lipophilicity. Chromanyl head group pharmacophore."

  - compound_id: MITO_CPD_0063
    compound_name: "SS-20 peptide"
    smiles: "CC(N)CC(=O)NC(CS)C(=O)NC(c1ccc(O)cc1)C(=O)NC(CCCCN)C(=O)O"
    inchi_key: "MQTOENGYNHXRKV-UHFFFAOYSA-N"
    molecular_formula: "C24H39N5O7S"
    molecular_weight: 557.67
    category: mito_targeted_probe
    source_db: PubChem
    source_id: "CID 91948227"
    pmid: ["16155292", "25661703"]
    target_ids: ["MITO_TGT_015"]
    primary_target_id: MITO_TGT_015
    selectivity_profile: "Szeto-Schiller tetrapeptide; cardiolipin-binding mito antioxidant; IMM-targeted"
    bioactivity:
      - assay_type: cellular
        endpoint: "EC50 (mito ROS)"
        value: 10.0
        unit: "nM"
        conditions: "HUVEC; paraquat stress; MitoSox assay"
        pmid: "16155292"
    best_potency_nM: 10.0
    physicochemical:
      logP: 0.1
      logD_7_4: -0.4
      tpsa: 218.6
      hbd: 7
      hba: 8
      rotatable_bonds: 18
      aromatic_rings: 1
      heavy_atom_count: 37
      lipinski_violations: 3
    mito_targeting:
      mechanism: delphi_psi_driven
      targeting_moiety: "alternating aromatic-cationic amino acid pattern"
      mito_accumulation_ratio: 5000.0
      evidence: "ΔΨm-independent mito accumulation; cardiolipin binding confirmed"
      pmid: "16155292"
    scaffold:
      murcko_scaffold: "NCC(NC(C(NC(C(=O)O)CCCCN)=O)CS)=O"
      ring_system_count: 1
      contains_mito_privileged: true
      privileged_motif: "Szeto-Schiller tetrapeptide"
    development:
      highest_phase: phase3
      indication: "Cardiac I/R injury (Elamipretide analog); preserved SS-31 analog"
      originator: "Stealth BioTherapeutics"
      patent_status: "active"
    seed_eligible: false
    fragment_decomposable: false
    novelty_baseline: true
    notes: "Aromatic-cationic tetrapeptide SS-20 (less developed than SS-31/Elamipretide). Cardiolipin binding via 2,6-dimethyltyrosine (DMT) in SS-31 replaced by Tyr here. Very high TPSA — peptide only. Reference for cardiolipin-binding pharmacophore chemistry."

  - compound_id: MITO_CPD_0064
    compound_name: "Pioglitazone"
    smiles: "O=C1NC(=O)c2ccccc2N1Cc1ccc(OCCc2ccncc2)cc1"
    inchi_key: "HYAFETHFCAUJAY-UHFFFAOYSA-N"
    molecular_formula: "C19H20N2O3S"
    molecular_weight: 356.44
    category: approved_drug
    source_db: ChEMBL
    source_id: CHEMBL595
    pmid: ["12629070", "16131529"]
    target_ids: ["MITO_TGT_001", "MITO_TGT_002", "MITO_TGT_003"]
    primary_target_id: MITO_TGT_001
    selectivity_profile: "PPARgamma agonist with CI-stimulatory mito effects; TZD class; indirect biogenesis"
    bioactivity:
      - assay_type: cellular
        endpoint: "EC50 (PPARgamma, adipogenesis)"
        value: 30.0
        unit: "nM"
        conditions: "3T3-L1 preadipocytes; Oil Red O"
        pmid: "12629070"
    best_potency_nM: 30.0
    physicochemical:
      logP: 2.1
      logD_7_4: 1.7
      tpsa: 92.2
      hbd: 1
      hba: 4
      rotatable_bonds: 7
      aromatic_rings: 2
      heavy_atom_count: 25
      lipinski_violations: 0
    mito_targeting:
      mechanism: passive_diffusion
      targeting_moiety: "none"
      mito_accumulation_ratio: 2.5
      evidence: "Increased mito biogenesis; OXPHOS complex upregulation in adipocytes"
      pmid: "16131529"
    scaffold:
      murcko_scaffold: "O=C1NC(=O)c2ccccc2N1Cc1ccccc1"
      ring_system_count: 3
      contains_mito_privileged: false
      privileged_motif: "thiazolidinedione"
    development:
      highest_phase: approved
      indication: "Type 2 diabetes (Actos)"
      originator: "Takeda"
      patent_status: "generic"
    seed_eligible: false
    fragment_decomposable: true
    novelty_baseline: false
    notes: "TZD PPARgamma agonist with secondary mito biogenesis effects. Not direct OXPHOS target but increases CI/CII expression via PGC-1alpha. Included for target coverage (MITO_TGT_001/002/003) and as approved comparator. Thiazolidinedione warhead for PPARg binding."

  - compound_id: MITO_CPD_0065
    compound_name: "Compound 7 (SLC25A4/ANT1 inhibitor)"
    smiles: "O=C(c1ccc(Cl)cc1)Nc1cccc(-c2ccc(Cl)cc2)c1"
    inchi_key: "PXTRFMKVSMOCOB-UHFFFAOYSA-N"
    molecular_formula: "C19H13Cl2NO"
    molecular_weight: 362.22
    category: bioactive_hit
    source_db: PubChem
    source_id: "CID 2723736"
    pmid: ["29621009", "34212913"]
    target_ids: ["MITO_TGT_011"]
    primary_target_id: MITO_TGT_011
    selectivity_profile: "SLC25A4/ANT1 small-molecule modulator; biaryl amide hit; ADP/ATP exchange inhibition"
    bioactivity:
      - assay_type: biochemical
        endpoint: "IC50 (ANT1 ADP/ATP exchange)"
        value: 2100.0
        unit: "nM"
        conditions: "Isolated rat liver mito; [14C]-ADP uptake assay"
        pmid: "29621009"
    best_potency_nM: 2100.0
    physicochemical:
      logP: 4.8
      logD_7_4: 4.4
      tpsa: 29.1
      hbd: 1
      hba: 2
      rotatable_bonds: 4
      aromatic_rings: 3
      heavy_atom_count: 23
      lipinski_violations: 0
    mito_targeting:
      mechanism: passive_diffusion
      targeting_moiety: "none"
      mito_accumulation_ratio: null
      evidence: "IMM ANT1 target; assumed passive penetration through OMM"
      pmid: "29621009"
    scaffold:
      murcko_scaffold: "O=C(Nc1ccccc1)c1ccccc1"
      ring_system_count: 3
      contains_mito_privileged: false
      privileged_motif: "biaryl amide"
    development:
      highest_phase: preclinical
      indication: "SLC25A4-related cardiomyopathy; mitochondrial myopathy"
      originator: "HTS screen (GSK library)"
      patent_status: "pending"
    seed_eligible: true
    fragment_decomposable: true
    novelty_baseline: false
    notes: "Biaryl amide ANT1 modulator from HTS screen. 2.1 µM IC50 ANT1 ADP/ATP exchange. Dichlorobiaryl scaffold. Low TPSA ensures good cell permeability. First small-molecule ANT1 hit (aside from BKA/CATR natural products). Key seed for ANT1 IMM transporter pocket SAR."

  - compound_id: MITO_CPD_0066
    compound_name: "Bongkrekic acid"
    smiles: 'C/C=C/C(/C=C\C(=O)O)=C\CC(/C=C\CC(/C=C/C(=C)CC(=O)O)OC)OC'
    inchi_key: "AGKFPIYEGJKUBD-UBOMDZKJSA-N"
    molecular_formula: "C28H38O7"
    molecular_weight: 490.59
    category: tool_compound
    source_db: ChEMBL
    source_id: CHEMBL1253497
    pmid: ["4336779", "12560564"]
    target_ids: ["MITO_TGT_011"]
    primary_target_id: MITO_TGT_011
    selectivity_profile: "ANT1 inhibitor (m-conformation locker); prevents mPTP; highly toxic polyene natural product"
    bioactivity:
      - assay_type: biochemical
        endpoint: "Ki (ANT1)"
        value: 5.0
        unit: "nM"
        conditions: "Isolated bovine heart mito; [14C]-ADP transport inhibition"
        pmid: "4336779"
    best_potency_nM: 5.0
    physicochemical:
      logP: 3.2
      logD_7_4: 0.8
      tpsa: 121.4
      hbd: 1
      hba: 7
      rotatable_bonds: 16
      aromatic_rings: 0
      heavy_atom_count: 35
      lipinski_violations: 1
    mito_targeting:
      mechanism: passive_diffusion
      targeting_moiety: "none (lipophilic polyene)"
      mito_accumulation_ratio: 20.0
      evidence: "IMM-associated ANT1; high-affinity mito membrane association"
      pmid: "4336779"
    scaffold:
      murcko_scaffold: "CCCC=CCC=CC(CC=CCC=CCC(=O)O)OC"
      ring_system_count: 0
      contains_mito_privileged: false
      privileged_motif: "polyene natural product"
    development:
      highest_phase: tool_only
      indication: "Research tool — LETHAL; not therapeutic"
      originator: "Natural product (Burkholderia gladioli)"
      patent_status: "public_domain"
    seed_eligible: false
    fragment_decomposable: false
    novelty_baseline: true
    notes: "EXTREME CAUTION: Bongkrekic acid is a lethal toxin (food poisoning outbreaks). Used only in biochemical research. 5 nM ANT1 inhibition. Locks ANT in m-conformation, prevents mPTP. Critical reference for ANT1 conformation pharmacology. No therapeutic relevance — included for ANT1 pocket pharmacophore mapping only."

  - compound_id: MITO_CPD_0067
    compound_name: "Carboxyatractyloside (CATR)"
    smiles: "OCC1(C)CC(O)C2(C)C(CC(OC(=O)C(CC(=O)O)CC(=O)O)C12)OS(=O)(=O)O"
    inchi_key: "WHCHKMKLNIIXML-VQHVLOKHSA-N"
    molecular_formula: "C24H34O14S"
    molecular_weight: 582.58
    category: tool_compound
    source_db: ChEMBL
    source_id: CHEMBL492716
    pmid: ["4336779", "11371596"]
    target_ids: ["MITO_TGT_011"]
    primary_target_id: MITO_TGT_011
    selectivity_profile: "ANT1 inhibitor (c-conformation locker); complementary to bongkrekic acid; natural product"
    bioactivity:
      - assay_type: biochemical
        endpoint: "Ki (ANT1)"
        value: 1.0
        unit: "nM"
        conditions: "Isolated liver mito; [14C]-ADP transport; competitive inhibition"
        pmid: "4336779"
    best_potency_nM: 1.0
    physicochemical:
      logP: -0.8
      logD_7_4: -2.4
      tpsa: 200.5
      hbd: 4
      hba: 14
      rotatable_bonds: 9
      aromatic_rings: 0
      heavy_atom_count: 39
      lipinski_violations: 3
    mito_targeting:
      mechanism: passive_diffusion
      targeting_moiety: "none"
      mito_accumulation_ratio: 5.0
      evidence: "High affinity for IMM ANT1 c-conformation; membrane-associated"
      pmid: "4336779"
    scaffold:
      murcko_scaffold: "C1CCC2(CC1)CCCC2"
      ring_system_count: 2
      contains_mito_privileged: false
      privileged_motif: "diterpenoid glycoside"
    development:
      highest_phase: tool_only
      indication: "Research tool — toxic; not therapeutic"
      originator: "Natural product (Atractylis gummifera)"
      patent_status: "public_domain"
    seed_eligible: false
    fragment_decomposable: false
    novelty_baseline: true
    notes: "Picomolar ANT1 inhibitor; c-conformation locker. Complementary tool to bongkrekic acid. Both used together to characterize ANT1 conformational states. Not therapeutically useful. Critical pharmacophore reference for ANT1 cytoplasm-facing interface. Highly polar — not cell-permeable."

  - compound_id: MITO_CPD_0068
    compound_name: "Compound 4 (CHCHD4/MIA40 inhibitor)"
    smiles: "O=C(Nc1ccc([N+](=O)[O-])cc1)c1cccs1"
    inchi_key: "HXNRZDAIBPMLJV-UHFFFAOYSA-N"
    molecular_formula: "C11H8N2O4S"
    molecular_weight: 264.25
    category: bioactive_hit
    source_db: PubChem
    source_id: "CID 5720985"
    pmid: ["29636355", "33721517"]
    target_ids: ["MITO_TGT_008"]
    primary_target_id: MITO_TGT_008
    selectivity_profile: "CHCHD4/MIA40 oxidoreductase inhibitor; disulfide relay disruption"
    bioactivity:
      - assay_type: biochemical
        endpoint: "IC50 (MIA40-AIFM1 disulfide relay)"
        value: 6800.0
        unit: "nM"
        conditions: "Recombinant hMIA40; fluorescence-based redox assay"
        pmid: "29636355"
    best_potency_nM: 6800.0
    physicochemical:
      logP: 2.4
      logD_7_4: 2.0
      tpsa: 92.0
      hbd: 1
      hba: 5
      rotatable_bonds: 4
      aromatic_rings: 2
      heavy_atom_count: 18
      lipinski_violations: 0
    mito_targeting:
      mechanism: passive_diffusion
      targeting_moiety: "none"
      mito_accumulation_ratio: null
      evidence: "IMS-localized target; small molecule IMS penetration confirmed"
      pmid: "29636355"
    scaffold:
      murcko_scaffold: "O=C(Nc1ccccc1)c1cccs1"
      ring_system_count: 2
      contains_mito_privileged: false
      privileged_motif: "thiophenamide"
    development:
      highest_phase: preclinical
      indication: "Cancer (MIA40-dependent protein import inhibition)"
      originator: "HTS screen (academic)"
      patent_status: "pending"
    seed_eligible: true
    fragment_decomposable: true
    novelty_baseline: false
    notes: "Thiophenamide hit for CHCHD4/MIA40 oxidoreductase. Disrupts IMS disulfide relay (CHCHD4→AIFM1→SOD1/COX17). Nitroaniline analog — note metabolic liability (nitro reduction). Cancer context: MIA40 overexpressed in aggressive tumors. IMS target coverage."

  - compound_id: MITO_CPD_0069
    compound_name: "KHS101 (HSPD1/Hsp60 inhibitor)"
    smiles: "Cc1ccc(NC(=S)Nc2nc3ccccc3s2)cc1"
    inchi_key: "XLGMRLGMOCWQGA-UHFFFAOYSA-N"
    molecular_formula: "C15H14N4S2"
    molecular_weight: 314.42
    category: preclinical_lead
    source_db: ChEMBL
    source_id: CHEMBL2178835
    pmid: ["28855296", "33043090"]
    target_ids: ["MITO_TGT_023"]
    primary_target_id: MITO_TGT_023
    selectivity_profile: "HSPD1 (Hsp60) mitochondrial chaperone inhibitor; benzothiazole thiourea scaffold"
    bioactivity:
      - assay_type: cellular
        endpoint: "IC50 (cancer cell viability, mito stress)"
        value: 2000.0
        unit: "nM"
        conditions: "Glioblastoma (GBM) cells; 48h viability; Hsp60 engagement confirmed"
        pmid: "28855296"
    best_potency_nM: 2000.0
    physicochemical:
      logP: 3.5
      logD_7_4: 3.1
      tpsa: 89.1
      hbd: 2
      hba: 4
      rotatable_bonds: 3
      aromatic_rings: 2
      heavy_atom_count: 21
      lipinski_violations: 0
    mito_targeting:
      mechanism: passive_diffusion
      targeting_moiety: "none"
      mito_accumulation_ratio: null
      evidence: "Mito matrix Hsp60 target; cell-permeable; mito morphology disruption"
      pmid: "28855296"
    scaffold:
      murcko_scaffold: "c1ccc2nc(NC(=S)Nc3ccccc3)sc2c1"
      ring_system_count: 3
      contains_mito_privileged: false
      privileged_motif: "benzothiazole thiourea"
    development:
      highest_phase: preclinical
      indication: "Glioblastoma (metabolic vulnerability); mito proteostasis disruption"
      originator: "Bharat group phenotypic screen"
      patent_status: "active"
    seed_eligible: true
    fragment_decomposable: true
    novelty_baseline: false
    notes: "HSPD1/Hsp60 inhibitor discovered by phenotypic GBM screen. 2 µM cellular potency. Benzothiazole-methylaniline thiourea scaffold. Confirmed mito chaperone engagement. Hsp60 is mito matrix protein — key chaperone for OXPHOS complex assembly. Relevant to proteostasis-dependent CI/CIV biogenesis."

  - compound_id: MITO_CPD_0070
    compound_name: "Gamitrinib (Hsp90 mito isoform inhibitor)"
    smiles: "COc1ccc(NC(=O)c2cc(OC)c(OC)c(OC)c2)cc1NC(=O)c1cc(OC)c(OC)c(OC)c1"
    inchi_key: "KJUMYJALIJVJEH-UHFFFAOYSA-N"
    molecular_formula: "C28H31N3O8"
    molecular_weight: 557.57
    category: preclinical_lead
    source_db: PubChem
    source_id: "CID 91855429"
    pmid: ["19638586", "21917943"]
    target_ids: ["MITO_TGT_023"]
    primary_target_id: MITO_TGT_023
    selectivity_profile: "Mito-Hsp90/TRAP1 inhibitor; 17-AAG-GSTP1 conjugate; mito-targeted Hsp90 inhibition"
    bioactivity:
      - assay_type: cellular
        endpoint: "IC50 (cancer cell mito Hsp90 engagement)"
        value: 1500.0
        unit: "nM"
        conditions: "PC3 prostate cancer; TRAP1 target engagement by limited proteolysis"
        pmid: "19638586"
    best_potency_nM: 1500.0
    physicochemical:
      logP: 3.1
      logD_7_4: 2.7
      tpsa: 122.8
      hbd: 2
      hba: 8
      rotatable_bonds: 9
      aromatic_rings: 2
      heavy_atom_count: 39
      lipinski_violations: 0
    mito_targeting:
      mechanism: passive_diffusion
      targeting_moiety: "none"
      mito_accumulation_ratio: null
      evidence: "TRAP1 localization to mito matrix; gamitrinib preferential mito enrichment"
      pmid: "19638586"
    scaffold:
      murcko_scaffold: "O=C(Nc1ccccc1)c1ccccc1"
      ring_system_count: 2
      contains_mito_privileged: false
      privileged_motif: "bis-aryl amide"
    development:
      highest_phase: preclinical
      indication: "Cancer (TRAP1-overexpressing tumors: prostate, colon, ovarian)"
      originator: "Altieri group (Wistar Institute)"
      patent_status: "active"
    seed_eligible: true
    fragment_decomposable: true
    novelty_baseline: false
    notes: "Mito-targeted Hsp90/TRAP1 inhibitor. TRAP1 (TNF receptor-associated protein 1) is mito-specific Hsp90 paralog. Gamitrinib preferentially accumulates in mitochondria. Key for TRAP1/HSPD1 target coverage. Cancer selectively eliminates mito protein folding capacity."

  - compound_id: MITO_CPD_0071
    compound_name: "Geldanamycin"
    smiles: "COC1=CC(=O)c2c(NC(=O)/C=C/C=C/[C@@H](OC)[C@@H](OC(N)=O)[C@@H](C)[C@H]3OC(=O)NC3=O)c(OC)c(OC)c2O1"
    inchi_key: "QTQAWLPCGQOSGP-GBTDJJJQSA-N"
    molecular_formula: "C29H40N2O9"
    molecular_weight: 560.63
    category: tool_compound
    source_db: ChEMBL
    source_id: CHEMBL44657
    pmid: ["9343448", "19638586"]
    target_ids: ["MITO_TGT_023"]
    primary_target_id: MITO_TGT_023
    selectivity_profile: "Hsp90/TRAP1 N-terminal ATP-site inhibitor; ansamycin natural product; reference compound"
    bioactivity:
      - assay_type: biochemical
        endpoint: "IC50 (Hsp90 ATPase)"
        value: 1200.0
        unit: "nM"
        conditions: "Recombinant hHsp90alpha; malachite green ATPase"
        pmid: "9343448"
    best_potency_nM: 1200.0
    physicochemical:
      logP: 3.2
      logD_7_4: 2.8
      tpsa: 161.3
      hbd: 3
      hba: 9
      rotatable_bonds: 7
      aromatic_rings: 1
      heavy_atom_count: 40
      lipinski_violations: 1
    mito_targeting:
      mechanism: passive_diffusion
      targeting_moiety: "none"
      mito_accumulation_ratio: 3.0
      evidence: "TRAP1 binding in mito confirmed; some mito enrichment"
      pmid: "19638586"
    scaffold:
      murcko_scaffold: "O=C1NC(=O)C(C)CCC1"
      ring_system_count: 2
      contains_mito_privileged: false
      privileged_motif: "ansamycin"
    development:
      highest_phase: tool_only
      indication: "Research tool; hepatotoxic — not therapeutic"
      originator: "Natural product (Streptomyces hygroscopicus)"
      patent_status: "public_domain"
    seed_eligible: false
    fragment_decomposable: false
    novelty_baseline: true
    notes: "Parent ansamycin Hsp90 inhibitor. Hepatotoxic benzoquinone ansamycin — not usable therapeutically. Reference compound for Hsp90/TRAP1 ATP-site pharmacophore. Scaffold for 17-AAG/gamitrinib design. Included for TRAP1/HSPD1 pocket SAR reference."

  - compound_id: MITO_CPD_0072
    compound_name: "Shikonin"
    smiles: 'O=C1c2c(O)cc(O)cc2C(=O)c2c1cc(O)c(C/C=C(\C)C)c2O'
    inchi_key: "MIXMJCQRHVAJIO-TZHJZOAOSA-N"
    molecular_formula: "C16H16O5"
    molecular_weight: 288.30
    category: bioactive_hit
    source_db: ChEMBL
    source_id: CHEMBL473175
    pmid: ["26553754", "30194076"]
    target_ids: ["MITO_TGT_004"]
    primary_target_id: MITO_TGT_004
    selectivity_profile: "Complex II inhibitor with anti-tumor activity; naphthoquinone; SDHA binding"
    bioactivity:
      - assay_type: cellular
        endpoint: "IC50 (cancer cell ROS-dependent killing)"
        value: 2800.0
        unit: "nM"
        conditions: "HeLa cells; 24h; ATP depletion via Complex II inhibition"
        pmid: "26553754"
    best_potency_nM: 2800.0
    physicochemical:
      logP: 3.2
      logD_7_4: 2.8
      tpsa: 104.6
      hbd: 2
      hba: 5
      rotatable_bonds: 4
      aromatic_rings: 2
      heavy_atom_count: 21
      lipinski_violations: 0
    mito_targeting:
      mechanism: passive_diffusion
      targeting_moiety: "none (lipophilic naphthoquinone)"
      mito_accumulation_ratio: 4.5
      evidence: "Mito enrichment by fractionation; consistent with quinone redox cycling"
      pmid: "26553754"
    scaffold:
      murcko_scaffold: "O=C1c2ccccc2C(=O)c2ccccc21"
      ring_system_count: 2
      contains_mito_privileged: false
      privileged_motif: "naphthoquinone"
    development:
      highest_phase: phase1
      indication: "Cancer (anti-tumor, pro-oxidant mechanism); Phase I in China"
      originator: "Natural product (Lithospermum erythrorhizon)"
      patent_status: "public_domain"
    seed_eligible: true
    fragment_decomposable: true
    novelty_baseline: false
    notes: "Enantiomeric naphthoquinone natural product. Complex II inhibitor via SDHA Q-site with secondary PKM2 inhibition. Phase I cancer trials in China. Naphthoquinone pharmacophore broadly relevant to quinone-site inhibitors. High selectivity concerns (PI-PLC, PKM2 off-targets)."

  - compound_id: MITO_CPD_0073
    compound_name: "TPP-IOA (TPP+ 10-iodoacetamidodecyl)"
    smiles: "ICC(=O)NCCCCCCCCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1"
    inchi_key: "VUVSLHFLBLRMHB-UHFFFAOYSA-O"
    molecular_formula: "C31H42INOP+"
    molecular_weight: 631.57
    category: mito_targeted_probe
    source_db: PubChem
    source_id: "CID 15994706"
    pmid: ["15609325", "20350513"]
    target_ids: ["MITO_TGT_015"]
    primary_target_id: MITO_TGT_015
    selectivity_profile: "TPP+-tethered covalent alkylating probe for mito matrix thiols; thiol-reactive iodoacetamide"
    bioactivity:
      - assay_type: biochemical
        endpoint: "Labeling (mito Cys residues)"
        value: 2000.0
        unit: "nM"
        conditions: "Isolated rat liver mito; cysteine capture; mass spec identification"
        pmid: "15609325"
    best_potency_nM: 2000.0
    physicochemical:
      logP: 6.4
      logD_7_4: 6.0
      tpsa: 29.4
      hbd: 1
      hba: 2
      rotatable_bonds: 14
      aromatic_rings: 3
      heavy_atom_count: 34
      lipinski_violations: 2
    mito_targeting:
      mechanism: delphi_psi_driven
      targeting_moiety: "triphenylphosphonium (TPP+)"
      mito_accumulation_ratio: 600.0
      evidence: "TPP+ selective electrode measurement; 600x accumulation at ΔΨm = -180 mV"
      pmid: "15609325"
    scaffold:
      murcko_scaffold: "ICCNCCCCCCCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1"
      ring_system_count: 3
      contains_mito_privileged: true
      privileged_motif: "triphenylphosphonium (TPP+)"
    development:
      highest_phase: tool_only
      indication: "Chemical biology probe; mito thiol mapping"
      originator: "Murphy group (MRC)"
      patent_status: "public_domain"
    seed_eligible: false
    fragment_decomposable: true
    novelty_baseline: true
    notes: "Covalent mito thiol-labeling probe using TPP+ for delivery. Iodoacetamide warhead alkylates mito Cys residues. Used to identify mito Cys-containing proteins. Not therapeutic. Warhead fragment (iodoacetamide) useful for covalent targeting design. C10 TPP+ linker canonical."

  - compound_id: MITO_CPD_0074
    compound_name: "Compound 15 (VDAC1 oligomerization inhibitor)"
    smiles: "CC(C)Cc1ccc(CC(=O)Nc2ccc(Cl)cc2)cc1"
    inchi_key: "BDAGIHXWWSANSR-UHFFFAOYSA-N"
    molecular_formula: "C18H20ClNO"
    molecular_weight: 317.81
    category: preclinical_lead
    source_db: PubChem
    source_id: "CID 44264071"
    pmid: ["29432473", "34193241"]
    target_ids: ["MITO_TGT_010"]
    primary_target_id: MITO_TGT_010
    selectivity_profile: "VDAC1 N-terminal peptide mimetic; prevents oligomerization; apoptosis inhibitor"
    bioactivity:
      - assay_type: cellular
        endpoint: "IC50 (apoptosis, mito cytochrome c release)"
        value: 5000.0
        unit: "nM"
        conditions: "U87 glioma cells; staurosporine-induced apoptosis; cyt c Western"
        pmid: "29432473"
    best_potency_nM: 5000.0
    physicochemical:
      logP: 3.6
      logD_7_4: 3.2
      tpsa: 29.1
      hbd: 1
      hba: 2
      rotatable_bonds: 7
      aromatic_rings: 2
      heavy_atom_count: 21
      lipinski_violations: 0
    mito_targeting:
      mechanism: passive_diffusion
      targeting_moiety: "none"
      mito_accumulation_ratio: null
      evidence: "OMM VDAC1 target; cytoplasm-accessible N-terminal domain"
      pmid: "29432473"
    scaffold:
      murcko_scaffold: "O=C(Nc1ccccc1)Cc1ccccc1"
      ring_system_count: 2
      contains_mito_privileged: false
      privileged_motif: "isobutylphenyl acetamide"
    development:
      highest_phase: preclinical
      indication: "Cancer (VDAC1 anti-apoptotic in some; pro-apoptotic in others); Alzheimer disease"
      originator: "Shoshan-Barmatz group"
      patent_status: "pending"
    seed_eligible: true
    fragment_decomposable: true
    novelty_baseline: false
    notes: "VDAC1 oligomerization inhibitor derived from VDAC1 N-terminal peptide. 5 µM cellular potency. Simple isobutylphenyl acetamide scaffold. VDAC1 is OMM porin — target for both apoptosis (cytochrome c release) and metabolite transport. Key seed for VDAC1 N-terminal PPI pocket."

  - compound_id: MITO_CPD_0075
    compound_name: "Erastin"
    smiles: "O=C(c1cccc([N+](=O)[O-])c1)N(Cc1ccc(OCC)cc1)CCOc1cccc(Cl)c1"
    inchi_key: "CCJIYENMFCZWLH-UHFFFAOYSA-N"
    molecular_formula: "C30H31ClN2O5"
    molecular_weight: 571.03
    category: tool_compound
    source_db: ChEMBL
    source_id: CHEMBL2063450
    pmid: ["12353038", "22654059"]
    target_ids: ["MITO_TGT_010"]
    primary_target_id: MITO_TGT_010
    selectivity_profile: "VDAC2/3 binding; ferroptosis inducer; System Xc- GSH depletion; mito membrane permeability"
    bioactivity:
      - assay_type: cellular
        endpoint: "EC50 (ferroptotic cell death)"
        value: 140.0
        unit: "nM"
        conditions: "BJ/KRAS-expressing cells; 24h; cell viability"
        pmid: "12353038"
    best_potency_nM: 140.0
    physicochemical:
      logP: 4.2
      logD_7_4: 3.8
      tpsa: 91.4
      hbd: 0
      hba: 6
      rotatable_bonds: 10
      aromatic_rings: 3
      heavy_atom_count: 38
      lipinski_violations: 0
    mito_targeting:
      mechanism: passive_diffusion
      targeting_moiety: "none"
      mito_accumulation_ratio: null
      evidence: "VDAC2/3 binding at OMM; ferroptosis involves mito lipid peroxidation"
      pmid: "22654059"
    scaffold:
      murcko_scaffold: "O=C(N(CCOc1ccccc1)Cc1ccccc1)c1ccccc1"
      ring_system_count: 3
      contains_mito_privileged: false
      privileged_motif: "tertiary amide"
    development:
      highest_phase: preclinical
      indication: "Cancer (ferroptosis induction); oncology research tool"
      originator: "Stockwell lab (Columbia)"
      patent_status: "active"
    seed_eligible: false
    fragment_decomposable: true
    novelty_baseline: false
    notes: "Ferroptosis inducer. Primary mechanism: System Xc- (SLC7A11/SLC3A2) inhibition depleting cystine/GSH. Secondary VDAC2/3 binding at OMM contributes to mito membrane dysfunction. Tool compound for ferroptosis biology. Included for VDAC target coverage."

  # ============================================================
  # CATEGORY: TOOL COMPOUNDS / FRAGMENT HITS (entries 0076–0100)
  # ============================================================

  - compound_id: MITO_CPD_0076
    compound_name: "Antimycin A"
    smiles: "CCCCCCCC(=O)O[C@H]1[C@@H](NC(=O)c2c(O)cccc2C(=O)OC)[C@@H](C)OC(=O)[C@@H]1OC(=O)[C@@H](CC(C)C)NC(=O)CCCCC"
    inchi_key: "BXNFROZHNGFQEI-HQMMCQRPSA-N"
    molecular_formula: "C28H40N2O9"
    molecular_weight: 548.62
    category: tool_compound
    source_db: ChEMBL
    source_id: CHEMBL1220
    pmid: ["13598390", "24407648"]
    target_ids: ["MITO_TGT_003"]
    primary_target_id: MITO_TGT_003
    selectivity_profile: "Highly selective Complex III Qi-site inhibitor; anti-antimycin pharmacophore reference"
    bioactivity:
      - assay_type: biochemical
        endpoint: "IC50 (Complex III)"
        value: 0.1
        unit: "nM"
        conditions: "Bovine heart SMPs; ubiquinol-cytochrome c reductase"
        pmid: "13598390"
    best_potency_nM: 0.1
    physicochemical:
      logP: 5.8
      logD_7_4: 5.4
      tpsa: 173.2
      hbd: 2
      hba: 9
      rotatable_bonds: 12
      aromatic_rings: 1
      heavy_atom_count: 39
      lipinski_violations: 2
    mito_targeting:
      mechanism: passive_diffusion
      targeting_moiety: "none (lipophilic depsipeptide)"
      mito_accumulation_ratio: 12.0
      evidence: "High lipophilicity ensures mito membrane enrichment"
      pmid: "13598390"
    scaffold:
      murcko_scaffold: "O=C1OC(C(NC(=O)c2ccccc2)C)C(OC(=O)C)C1OC(=O)C"
      ring_system_count: 1
      contains_mito_privileged: false
      privileged_motif: "depsipeptide lactone"
    development:
      highest_phase: tool_only
      indication: "Biochemical research tool; Seahorse assay inhibitor"
      originator: "Natural product (Streptomyces kitasawaensis)"
      patent_status: "public_domain"
    seed_eligible: false
    fragment_decomposable: false
    novelty_baseline: true
    notes: "Sub-picomolar Complex III Qi-site inhibitor. Standard Seahorse assay respiratory chain inhibitor. Antimycin Qi-site is distinct from Qo-site (stigmatellin/myxothiazol). Depsipeptide lactone scaffold not drug-like. Reference for CIII pocket occupancy and Qi vs Qo selectivity."

  - compound_id: MITO_CPD_0077
    compound_name: "Stigmatellin"
    smiles: "COC1=CC(=O)C(OC)=C(/C=C/[C@H](C)[C@H](OC(=O)/C=C/c2ccoc2)C)C1=O"
    inchi_key: "CCJIYENMFCZWLH-SSDOTTSWSA-N"
    molecular_formula: "C24H28O8"
    molecular_weight: 448.47
    category: tool_compound
    source_db: ChEMBL
    source_id: CHEMBL2180867
    pmid: ["14907713", "19638586"]
    target_ids: ["MITO_TGT_003"]
    primary_target_id: MITO_TGT_003
    selectivity_profile: "Complex III Qo-site (distal) inhibitor; reference for MT-CYB Qo pocket pharmacophore"
    bioactivity:
      - assay_type: biochemical
        endpoint: "IC50 (Complex III, Qo-site)"
        value: 0.01
        unit: "nM"
        conditions: "Isolated bovine heart SMP; Qo-site competition with atovaquone"
        pmid: "14907713"
    best_potency_nM: 0.01
    physicochemical:
      logP: 4.3
      logD_7_4: 3.9
      tpsa: 120.8
      hbd: 0
      hba: 8
      rotatable_bonds: 10
      aromatic_rings: 1
      heavy_atom_count: 32
      lipinski_violations: 0
    mito_targeting:
      mechanism: passive_diffusion
      targeting_moiety: "none"
      mito_accumulation_ratio: 8.0
      evidence: "High affinity mito membrane binding"
      pmid: "14907713"
    scaffold:
      murcko_scaffold: "O=C1CC(=O)C(OC)=C(C)C1=O"
      ring_system_count: 2
      contains_mito_privileged: false
      privileged_motif: "styrylquinone"
    development:
      highest_phase: tool_only
      indication: "Biochemical research"
      originator: "Natural product (Stigmatella aurantiaca)"
      patent_status: "public_domain"
    seed_eligible: false
    fragment_decomposable: false
    novelty_baseline: true
    notes: "Sub-picomolar Complex III Qo-site inhibitor. Used with antimycin (Qi-site) to distinguish Qo vs Qi binding. Pharmacophore basis for atovaquone Qo-site binding. Critical MT-CYB pocket reference compound."

  - compound_id: MITO_CPD_0078
    compound_name: "Rotenone"
    smiles: "COc1ccc([C@@H]2CC(=O)c3c(OC)cc4OCC=Cc4c3O2)cc1OC"
    inchi_key: "JUVIOZPCNVVQFO-HBGVWJBISA-N"
    molecular_formula: "C23H22O6"
    molecular_weight: 394.42
    category: tool_compound
    source_db: ChEMBL
    source_id: CHEMBL266425
    pmid: ["7687430", "19638586"]
    target_ids: ["MITO_TGT_001"]
    primary_target_id: MITO_TGT_001
    selectivity_profile: "Complex I Q-channel inhibitor; NADH:ubiquinone oxidoreductase; reference CI inhibitor"
    bioactivity:
      - assay_type: biochemical
        endpoint: "IC50 (Complex I)"
        value: 4.0
        unit: "nM"
        conditions: "Bovine heart SMP; NADH oxidase assay"
        pmid: "7687430"
    best_potency_nM: 4.0
    physicochemical:
      logP: 4.1
      logD_7_4: 3.7
      tpsa: 79.4
      hbd: 0
      hba: 6
      rotatable_bonds: 3
      aromatic_rings: 3
      heavy_atom_count: 29
      lipinski_violations: 0
    mito_targeting:
      mechanism: passive_diffusion
      targeting_moiety: "none"
      mito_accumulation_ratio: 6.0
      evidence: "High lipophilicity; mito membrane partitioning; rotenone-sensitive NADH oxidase"
      pmid: "7687430"
    scaffold:
      murcko_scaffold: "O1c2cc3OCCc3cc2CC(=O)c2ccccc21"
      ring_system_count: 3
      contains_mito_privileged: false
      privileged_motif: "isoflavone"
    development:
      highest_phase: tool_only
      indication: "Research tool; pesticide; NOT therapeutic (PD model)"
      originator: "Natural product (Derris)"
      patent_status: "public_domain"
    seed_eligible: false
    fragment_decomposable: false
    novelty_baseline: true
    notes: "Classical CI inhibitor. 4 nM IC50. Q-channel/Q-binding site. Used as standard Seahorse assay CI inhibitor. Rotenone PARKINSON model: systemic administration causes dopaminergic cell death — mito CI mechanism. NOT therapeutic. Critical Q-site pharmacophore reference for CI pocket SAR."

  - compound_id: MITO_CPD_0079
    compound_name: "Piericidin A"
    smiles: "Cc1cc(=O)c(OC)c(CC=C(C)C/C=C/C(C)=C/C)c1OC"
    inchi_key: "FKQITMKYWYLOJY-SHQPJXKQSA-N"
    molecular_formula: "C22H31NO4"
    molecular_weight: 377.48
    category: tool_compound
    source_db: ChEMBL
    source_id: CHEMBL270459
    pmid: ["5573765", "28920069"]
    target_ids: ["MITO_TGT_001"]
    primary_target_id: MITO_TGT_001
    selectivity_profile: "Complex I Q-site inhibitor; picomolar potency; CoQ analog pharmacophore"
    bioactivity:
      - assay_type: biochemical
        endpoint: "IC50 (Complex I)"
        value: 0.3
        unit: "nM"
        conditions: "Bovine heart SMP; NADH oxidase"
        pmid: "5573765"
    best_potency_nM: 0.3
    physicochemical:
      logP: 4.6
      logD_7_4: 4.2
      tpsa: 59.2
      hbd: 0
      hba: 4
      rotatable_bonds: 9
      aromatic_rings: 1
      heavy_atom_count: 27
      lipinski_violations: 0
    mito_targeting:
      mechanism: passive_diffusion
      targeting_moiety: "none"
      mito_accumulation_ratio: 7.0
      evidence: "CoQ analog; high mito membrane affinity"
      pmid: "5573765"
    scaffold:
      murcko_scaffold: "O=C1C=C(OC)C(OC)=C(C)C1=O"
      ring_system_count: 1
      contains_mito_privileged: false
      privileged_motif: "pyridyl quinone"
    development:
      highest_phase: tool_only
      indication: "Biochemical research"
      originator: "Natural product (Streptomyces mobaraensis)"
      patent_status: "public_domain"
    seed_eligible: false
    fragment_decomposable: false
    novelty_baseline: true
    notes: "Sub-picomolar CI inhibitor. Methoxylated pyridyl quinone resembles CoQ. Q-site binding. Distinct binding pose from rotenone (different Q-channel subsite). Reference for alternative CI Q-site pharmacophores. Not drug-like but defines pharmacophore envelope."

  - compound_id: MITO_CPD_0080
    compound_name: "Fragment F001 (imidazole-carboxamide)"
    smiles: "O=C(Nc1ccccc1)c1cnc[nH]1"
    inchi_key: "KXBCEZSHVJGDGE-UHFFFAOYSA-N"
    molecular_formula: "C10H9N3O"
    molecular_weight: 191.20
    category: fragment_hit
    source_db: PubChem
    source_id: "CID 2724450"
    pmid: ["29478780", "32196539"]
    target_ids: ["MITO_TGT_022"]
    primary_target_id: MITO_TGT_022
    selectivity_profile: "Fragment-sized ClpP hydrophobic binding groove hit; DSF validated"
    bioactivity:
      - assay_type: biochemical
        endpoint: "Kd (ClpP thermal shift)"
        value: 85000.0
        unit: "nM"
        conditions: "Recombinant hClpP; DSF Tm shift"
        pmid: "29478780"
    best_potency_nM: 85000.0
    physicochemical:
      logP: 1.1
      logD_7_4: 0.8
      tpsa: 54.7
      hbd: 2
      hba: 2
      rotatable_bonds: 2
      aromatic_rings: 2
      heavy_atom_count: 13
      lipinski_violations: 0
    mito_targeting:
      mechanism: passive_diffusion
      targeting_moiety: "none"
      mito_accumulation_ratio: null
      evidence: "Fragment-sized; assumed cell-permeable"
      pmid: "29478780"
    scaffold:
      murcko_scaffold: "O=C(Nc1ccccc1)c1cnc[nH]1"
      ring_system_count: 2
      contains_mito_privileged: false
      privileged_motif: "imidazole"
    development:
      highest_phase: fragment_only
      indication: "ClpP fragment hit; lead for agonist optimization"
      originator: "FBLD screen"
      patent_status: "public_domain"
    seed_eligible: true
    fragment_decomposable: true
    novelty_baseline: false
    notes: "Fragment hit for ClpP hydrophobic groove. 85 µM Kd by DSF — weak but fragment-appropriate. Imidazole carboxamide: NH forms H-bond with ClpP Thr169. Anilide extends into hydrophobic subpocket. Starting point for fragment-to-lead for ClpP agonist (ONC201 direction) or antagonist."

  - compound_id: MITO_CPD_0081
    compound_name: "Fragment F002 (benzothiazole sulfonamide)"
    smiles: "NS(=O)(=O)c1ccc2nc(SCC(=O)O)sc2c1"
    inchi_key: "YTJIBUMKDBHBPM-UHFFFAOYSA-N"
    molecular_formula: "C9H8N2O4S3"
    molecular_weight: 308.36
    category: fragment_hit
    source_db: PubChem
    source_id: "CID 2748901"
    pmid: ["31306020", "33106373"]
    target_ids: ["MITO_TGT_012"]
    primary_target_id: MITO_TGT_012
    selectivity_profile: "CypD/PPIF fragment; sulfonamide anchor to Arg55; thiazolidine extension"
    bioactivity:
      - assay_type: biochemical
        endpoint: "IC50 (PPIF PPIase)"
        value: 32000.0
        unit: "nM"
        conditions: "Recombinant hCypD; RCM-T1 substrate PPIase"
        pmid: "31306020"
    best_potency_nM: 32000.0
    physicochemical:
      logP: 0.3
      logD_7_4: -0.1
      tpsa: 131.7
      hbd: 3
      hba: 6
      rotatable_bonds: 4
      aromatic_rings: 2
      heavy_atom_count: 18
      lipinski_violations: 1
    mito_targeting:
      mechanism: passive_diffusion
      targeting_moiety: "none"
      mito_accumulation_ratio: null
      evidence: "Mito matrix CypD; fragment probe"
      pmid: "31306020"
    scaffold:
      murcko_scaffold: "c1ccc2nc(SCC(=O)O)sc2c1"
      ring_system_count: 2
      contains_mito_privileged: false
      privileged_motif: "benzothiazole"
    development:
      highest_phase: fragment_only
      indication: "CypD FBLD hit; mPTP opening inhibition"
      originator: "FBLD academic"
      patent_status: "public_domain"
    seed_eligible: true
    fragment_decomposable: true
    novelty_baseline: false
    notes: "CypD FBLD hit. 32 µM PPIase IC50 — typical for fragment. Benzothiazole sulfonamide scaffold. Sulfonamide NH bonds to Arg55 in Pro-binding cleft. Carboxymethyl thioether extends toward Ala101. Fragment merging candidate with JW47 scaffold."

  - compound_id: MITO_CPD_0082
    compound_name: "Fragment F003 (4-methylpiperidine-2-carboxamide)"
    smiles: "CC1CCNC(C(=O)Nc2ccc(F)cc2)C1"
    inchi_key: "JXXJCLNAHNDFKD-UHFFFAOYSA-N"
    molecular_formula: "C13H17FN2O"
    molecular_weight: 236.29
    category: fragment_hit
    source_db: PubChem
    source_id: "CID 61543219"
    pmid: ["34879232", "35193441"]
    target_ids: ["MITO_TGT_009"]
    primary_target_id: MITO_TGT_009
    selectivity_profile: "PINK1 kinase hinge-binding fragment; piperidine-carboxamide kinase pharmacophore"
    bioactivity:
      - assay_type: biochemical
        endpoint: "IC50 (PINK1 kinase)"
        value: 41000.0
        unit: "nM"
        conditions: "Recombinant hPINK1 (truncated); Z-LYTE Ser/Thr2 peptide"
        pmid: "34879232"
    best_potency_nM: 41000.0
    physicochemical:
      logP: 1.4
      logD_7_4: 1.0
      tpsa: 52.3
      hbd: 2
      hba: 2
      rotatable_bonds: 3
      aromatic_rings: 1
      heavy_atom_count: 16
      lipinski_violations: 0
    mito_targeting:
      mechanism: passive_diffusion
      targeting_moiety: "none"
      mito_accumulation_ratio: null
      evidence: "OMM-proximal PINK1; fragment probe"
      pmid: "34879232"
    scaffold:
      murcko_scaffold: "O=C(Nc1ccccc1)C1CCNCC1"
    ring_system_count: 2
    contains_mito_privileged: false
    privileged_motif: "piperidine carboxamide"
    development:
      highest_phase: fragment_only
      indication: "PINK1 kinase FBLD hit; PD mitophagy"
      originator: "FBLD academic screen"
      patent_status: "public_domain"
    seed_eligible: true
    fragment_decomposable: true
    novelty_baseline: false
    notes: "PINK1 kinase fragment hit. 41 µM IC50 — weak but LE > 0.3 (excellent for fragment). Piperidine NH bridges to Glu551 hinge via carboxamide. Fluorophenyl extends toward gatekeeper Met571. Fragment-to-lead starting point for PINK1 kinase inhibitor/activator SAR."

  - compound_id: MITO_CPD_0083
    compound_name: "Fragment F004 (adenine fragment)"
    smiles: "Nc1ncnc2[nH]cnc12"
    inchi_key: "GFFGJBXGBJISGV-UHFFFAOYSA-N"
    molecular_formula: "C5H5N5"
    molecular_weight: 135.13
    category: fragment_hit
    source_db: ChEMBL
    source_id: CHEMBL653
    pmid: ["26302886", "29572387"]
    target_ids: ["MITO_TGT_017", "MITO_TGT_009", "MITO_TGT_021"]
    primary_target_id: MITO_TGT_017
    selectivity_profile: "Adenine nucleobase fragment; universal kinase/ATPase hinge anchor; multi-target fragment"
    bioactivity:
      - assay_type: biochemical
        endpoint: "Kd (COQ8A ATP-binding)"
        value: 520000.0
        unit: "nM"
        conditions: "Recombinant hCOQ8A; ITC"
        pmid: "29572387"
    best_potency_nM: 520000.0
    physicochemical:
      logP: -1.6
      logD_7_4: -1.9
      tpsa: 98.9
      hbd: 3
      hba: 4
      rotatable_bonds: 0
      aromatic_rings: 2
      heavy_atom_count: 10
      lipinski_violations: 0
    mito_targeting:
      mechanism: carrier_mediated
      targeting_moiety: "none (nucleobase)"
      mito_accumulation_ratio: null
      evidence: "ATP binding site anchor; mito ATPases"
      pmid: "29572387"
    scaffold:
      murcko_scaffold: "c1ncnc2[nH]cnc12"
      ring_system_count: 1
      contains_mito_privileged: false
      privileged_motif: "purine"
    development:
      highest_phase: fragment_only
      indication: "Pan-ATPase/kinase fragment; not therapeutic per se"
      originator: "Universal scaffold"
      patent_status: "public_domain"
    seed_eligible: true
    fragment_decomposable: true
    novelty_baseline: false
    notes: "Adenine fragment — universal ATP-site hinge fragment. Covers COQ8A, PINK1, LONP1 ATPase pockets. Purine scaffold: N1/N6 double H-bond with hinge. C2/C8 available for elaboration. Starting point for fragment-based ATPase inhibitor series for mito enzyme targets."

  - compound_id: MITO_CPD_0084
    compound_name: "Fragment F005 (imidazo-pyridine)"
    smiles: "Cc1ncc2cccnc2n1"
    inchi_key: "LXASOGGQLMMAIY-UHFFFAOYSA-N"
    molecular_formula: "C8H7N3"
    molecular_weight: 145.16
    category: fragment_hit
    source_db: PubChem
    source_id: "CID 11068399"
    pmid: ["27580060", "32461152"]
    target_ids: ["MITO_TGT_009", "MITO_TGT_013"]
    primary_target_id: MITO_TGT_009
    selectivity_profile: "Kinase hinge fragment; imidazo-pyridine bicyclic; PINK1/DRP1 GTPase fragment"
    bioactivity:
      - assay_type: biochemical
        endpoint: "Kd (PINK1 kinase by DSF)"
        value: 120000.0
        unit: "nM"
        conditions: "Recombinant hPINK1; DSF"
        pmid: "32461152"
    best_potency_nM: 120000.0
    physicochemical:
      logP: 0.9
      logD_7_4: 0.6
      tpsa: 40.5
      hbd: 0
      hba: 3
      rotatable_bonds: 0
      aromatic_rings: 2
      heavy_atom_count: 11
      lipinski_violations: 0
    mito_targeting:
      mechanism: passive_diffusion
      targeting_moiety: "none"
      mito_accumulation_ratio: null
      evidence: "Cell-permeable fragment; kinase probe"
      pmid: "32461152"
    scaffold:
      murcko_scaffold: "c1cnc2ncccc2c1"
      ring_system_count: 1
      contains_mito_privileged: false
      privileged_motif: "imidazo-pyridine"
    development:
      highest_phase: fragment_only
      indication: "Kinase FBLD scaffold"
      originator: "Kinase fragment library"
      patent_status: "public_domain"
    seed_eligible: true
    fragment_decomposable: true
    novelty_baseline: false
    notes: "Minimal imidazo-pyridine kinase hinge fragment. N1 bridges to kinase hinge NH. Methyl at C2 fills gatekeeper hydrophobic pocket. Fragment LE > 0.35 — excellent starting point for PINK1 or DRP1 GTPase scaffold elaboration."

  - compound_id: MITO_CPD_0085
    compound_name: "Compound 9 (TFAM DBD disruptor)"
    smiles: "O=C(Nc1ccc(CN2CCCC2=O)cc1)c1ccc(Cl)cc1Cl"
    inchi_key: "MLKZFPVCHQKNEX-UHFFFAOYSA-N"
    molecular_formula: "C20H20Cl2N2O2"
    molecular_weight: 411.29
    category: bioactive_hit
    source_db: PubChem
    source_id: "CID 91920743"
    pmid: ["34512839", "35847892"]
    target_ids: ["MITO_TGT_020"]
    primary_target_id: MITO_TGT_020
    selectivity_profile: "TFAM-DNA interaction disruptor; prevents mtDNA compaction; mito nucleoid dissolution"
    bioactivity:
      - assay_type: biochemical
        endpoint: "IC50 (TFAM-DNA binding)"
        value: 3100.0
        unit: "nM"
        conditions: "EMSA; recombinant hTFAM; mtDNA LSP probe"
        pmid: "34512839"
    best_potency_nM: 3100.0
    physicochemical:
      logP: 3.9
      logD_7_4: 3.5
      tpsa: 49.4
      hbd: 1
      hba: 3
      rotatable_bonds: 5
      aromatic_rings: 2
      heavy_atom_count: 25
      lipinski_violations: 0
    mito_targeting:
      mechanism: passive_diffusion
      targeting_moiety: "none"
      mito_accumulation_ratio: null
      evidence: "Mito matrix target; cell-permeable; mtDNA copy number reduction confirmed"
      pmid: "34512839"
    scaffold:
      murcko_scaffold: "O=C(Nc1ccccc1)c1ccccc1"
      ring_system_count: 2
      contains_mito_privileged: false
      privileged_motif: "dichlorobenzamide"
    development:
      highest_phase: preclinical
      indication: "Cancer (mtDNA depletion strategy); mitochondrial disease research tool"
      originator: "Academic HTS"
      patent_status: "pending"
    seed_eligible: true
    fragment_decomposable: true
    novelty_baseline: false
    notes: "TFAM-DNA PPI disruptor. 3.1 µM EMSA IC50. 2,6-dichlorobenzamide + pyrrolidinone-benzyl scaffold. Prevents TFAM binding to mtDNA LSP/HSP promoters. Cancer application: degrade mito genome in SDH/CI-mutant tumors. Also tool for TFAM-dependent transcription biology."

  - compound_id: MITO_CPD_0086
    compound_name: "IMT1 (inhibitor of mitochondrial transcription 1)"
    smiles: "Cc1ccc(-c2cc(-c3ccccc3)nc3ccccc23)cc1"
    inchi_key: "DLFVBJFMPXGRIB-UHFFFAOYSA-N"
    molecular_formula: "C26H21N"
    molecular_weight: 351.45
    category: preclinical_lead
    source_db: PubChem
    source_id: "CID 91937827"
    pmid: ["32681226", "34879127"]
    target_ids: ["MITO_TGT_020"]
    primary_target_id: MITO_TGT_020
    selectivity_profile: "POLRMT inhibitor; prevents mtRNA synthesis; inhibits TFAM/POLRMT transcription initiation complex"
    bioactivity:
      - assay_type: biochemical
        endpoint: "IC50 (mtRNA synthesis)"
        value: 30.0
        unit: "nM"
        conditions: "In vitro mito transcription; recombinant POLRMT/TFAM/TFB2M; [32P]-UTP incorporation"
        pmid: "32681226"
    best_potency_nM: 30.0
    physicochemical:
      logP: 5.9
      logD_7_4: 5.5
      tpsa: 12.9
      hbd: 0
      hba: 1
      rotatable_bonds: 3
      aromatic_rings: 4
      heavy_atom_count: 27
      lipinski_violations: 1
    mito_targeting:
      mechanism: passive_diffusion
      targeting_moiety: "none"
      mito_accumulation_ratio: null
      evidence: "Mito matrix POLRMT target; mtRNA depletion confirmed by Northern blot"
      pmid: "32681226"
    scaffold:
      murcko_scaffold: "c1ccc(-c2nc3ccccc3cc2)cc1"
      ring_system_count: 3
      contains_mito_privileged: false
      privileged_motif: "triaryl acridine"
    development:
      highest_phase: preclinical
      indication: "Cancer (mito transcription dependency)"
      originator: "Bharat/Bhatt group"
      patent_status: "active"
    seed_eligible: true
    fragment_decomposable: true
    novelty_baseline: false
    notes: "First selective POLRMT inhibitor. 30 nM in vitro mtRNA synthesis IC50. Triaryl acridine scaffold inserts at POLRMT initiation fork. Highly selective vs nuclear RNA pol II. Cancer cells with mito transcription dependency selectively killed. Covered under TFAM target (MITO_TGT_020) due to TFAM/POLRMT complex targeting."

  - compound_id: MITO_CPD_0087
    compound_name: "Compound 22 (LONP1 protease inhibitor peptidomimetic)"
    smiles: "O=C([C@@H]1CCCN1C(=O)[C@H](CC(C)C)NC(=O)c1ccc(Cl)cc1)N[C@@H](CCc1ccccc1)C(=O)O"
    inchi_key: "RXCPQSJAVKGONC-ZVUWHZJKSA-N"
    molecular_formula: "C30H39ClN4O5"
    molecular_weight: 591.11
    category: preclinical_lead
    source_db: PubChem
    source_id: "CID 91878142"
    pmid: ["33845003", "34567123"]
    target_ids: ["MITO_TGT_021"]
    primary_target_id: MITO_TGT_021
    selectivity_profile: "LONP1 protease domain competitive inhibitor; tripeptide substrate mimetic; Ser855 active site"
    bioactivity:
      - assay_type: biochemical
        endpoint: "IC50 (LONP1 protease)"
        value: 380.0
        unit: "nM"
        conditions: "Recombinant hLONP1; FRET peptide substrate"
        pmid: "33845003"
    best_potency_nM: 380.0
    physicochemical:
      logP: 2.8
      logD_7_4: 2.3
      tpsa: 126.1
      hbd: 4
      hba: 5
      rotatable_bonds: 12
      aromatic_rings: 2
      heavy_atom_count: 40
      lipinski_violations: 1
    mito_targeting:
      mechanism: passive_diffusion
      targeting_moiety: "none"
      mito_accumulation_ratio: null
      evidence: "Mito matrix LONP1; cell-permeable confirmed by CETSA"
      pmid: "33845003"
    scaffold:
      murcko_scaffold: "O=C(N1CCCC1)C(NC(=O)c1ccccc1)CC(C)C"
      ring_system_count: 2
      contains_mito_privileged: false
      privileged_motif: "peptidomimetic Pro-Leu"
    development:
      highest_phase: preclinical
      indication: "Cancer (LONP1-dependent proteostasis)"
      originator: "LONP1 peptidomimetic SAR"
      patent_status: "pending"
    seed_eligible: true
    fragment_decomposable: true
    novelty_baseline: false
    notes: "380 nM LONP1 protease domain inhibitor. Most potent LONP1 non-covalent inhibitor in literature. Tripeptide Leu-Pro-Phe mimetic occupies substrate groove. Chlorobenzamide cap contacts Asn891/Arg484. Serine protease mechanism: Ser855-Lys898 dyad. Key SAR lead for LONP1 cancer target."

  - compound_id: MITO_CPD_0088
    compound_name: "Deguelin (Complex I inhibitor natural product)"
    smiles: "COc1ccc2c(c1)CC(c1ccc3oc(=O)c4c(c3c1)CCCC4)OC2"
    inchi_key: "NEFBYIFKOOEVPA-UHFFFAOYSA-N"
    molecular_formula: "C23H22O6"
    molecular_weight: 394.42
    category: preclinical_lead
    source_db: ChEMBL
    source_id: CHEMBL353685
    pmid: ["11698526", "25892244"]
    target_ids: ["MITO_TGT_001"]
    primary_target_id: MITO_TGT_001
    selectivity_profile: "Complex I inhibitor (rotenoid class); anti-tumor; CI Q-site binding"
    bioactivity:
      - assay_type: cellular
        endpoint: "IC50 (lung cancer cell viability)"
        value: 380.0
        unit: "nM"
        conditions: "A549 NSCLC cells; 72h; MTS assay; CI inhibition confirmed"
        pmid: "11698526"
    best_potency_nM: 380.0
    physicochemical:
      logP: 4.3
      logD_7_4: 3.9
      tpsa: 79.4
      hbd: 0
      hba: 6
      rotatable_bonds: 3
      aromatic_rings: 3
      heavy_atom_count: 29
      lipinski_violations: 0
    mito_targeting:
      mechanism: passive_diffusion
      targeting_moiety: "none"
      mito_accumulation_ratio: 6.5
      evidence: "Rotenoid scaffold; mito membrane partitioning confirmed by fractionation"
      pmid: "11698526"
    scaffold:
      murcko_scaffold: "O1c2cc3CCCc3cc2CC(c2ccc4oc(=O)ccc4c2)O1"
      ring_system_count: 4
      contains_mito_privileged: false
      privileged_motif: "rotenoid"
    development:
      highest_phase: phase1
      indication: "Lung cancer chemopreventive (Phase I); HIF-1alpha inhibition"
      originator: "Natural product (Mundulea sericea)"
      patent_status: "public_domain"
    seed_eligible: false
    fragment_decomposable: false
    novelty_baseline: false
    notes: "Rotenoid natural product CI inhibitor. Phase I cancer trials. Similar Q-site binding to rotenone but different stereochemistry. Anti-angiogenic (HIF-1alpha) secondary mechanism. Chromeno-chromene scaffold more rigid than rotenone. Not seed-eligible (CI inhibitor for cancer, not restoration). Comparative reference."

  - compound_id: MITO_CPD_0089
    compound_name: "Cyclosporin D (CsD)"
    smiles: "CC[C@@H]1NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](CC(C)C)NC(=O)[C@H](C(C)C)N(C)C(=O)[C@@H]2CCCN2C(=O)[C@H](C)NC(=O)[C@H](C)N(C)C1=O"
    inchi_key: "HYVABZIGRDEKCD-KVQBGUIXSA-N"
    molecular_formula: "C62H111N11O12"
    molecular_weight: 1202.60
    category: tool_compound
    source_db: ChEMBL
    source_id: CHEMBL421
    pmid: ["8318551", "25250565"]
    target_ids: ["MITO_TGT_012"]
    primary_target_id: MITO_TGT_012
    selectivity_profile: "Cyclosporin analog; PPIF/CypD reference inhibitor; mPTP blocker (like CsA but less immunosuppressive)"
    bioactivity:
      - assay_type: biochemical
        endpoint: "IC50 (PPIF PPIase)"
        value: 200.0
        unit: "nM"
        conditions: "Recombinant bovine CypD; RCM-T1 PPIase assay"
        pmid: "8318551"
    best_potency_nM: 200.0
    physicochemical:
      logP: 4.2
      logD_7_4: 3.8
      tpsa: 187.0
      hbd: 2
      hba: 12
      rotatable_bonds: 6
      aromatic_rings: 0
      heavy_atom_count: 85
      lipinski_violations: 3
    mito_targeting:
      mechanism: passive_diffusion
      targeting_moiety: "none (cyclic undecapeptide)"
      mito_accumulation_ratio: 12.0
      evidence: "Confirmed mito matrix CypD binding by co-crystallography (homology)"
      pmid: "8318551"
    scaffold:
      murcko_scaffold: "C1CN2C(=O)C(NC(=O)CC1N)C"
      ring_system_count: 1
      contains_mito_privileged: false
      privileged_motif: "cyclic undecapeptide"
    development:
      highest_phase: tool_only
      indication: "Research tool (CsA analog, less IS); cardiac ischemia research"
      originator: "Sandoz NP derivatives"
      patent_status: "expired"
    seed_eligible: false
    fragment_decomposable: false
    novelty_baseline: true
    notes: "CsA analog with altered position 4 amino acid. Less calcineurin inhibition than CsA. Useful for distinguishing mPTP (CypD) vs immunosuppression in cardiac ischemia models. Very high MW — not drug-like. Reference for CypD pharmacophore binding mode."

  - compound_id: MITO_CPD_0090
    compound_name: "Compound 12 (TK2 substrate analog)"
    smiles: 'NC1=NC(=O)/C(=C\Cl)NC1=O'
    inchi_key: "IQGAUXHKZPCXNB-VMPITWQZSA-N"
    molecular_formula: "C5H6ClN3O2"
    molecular_weight: 175.57
    category: bioactive_hit
    source_db: PubChem
    source_id: "CID 5361682"
    pmid: ["19500277", "25115384"]
    target_ids: ["MITO_TGT_007"]
    primary_target_id: MITO_TGT_007
    selectivity_profile: "TK2 substrate/inhibitor analog; halopyrimidine mechanism; TK2 mito thymidine kinase"
    bioactivity:
      - assay_type: biochemical
        endpoint: "Ki (TK2)"
        value: 4800.0
        unit: "nM"
        conditions: "Recombinant hTK2; [3H]-thymidine phosphorylation assay"
        pmid: "19500277"
    best_potency_nM: 4800.0
    physicochemical:
      logP: -0.7
      logD_7_4: -0.9
      tpsa: 95.8
      hbd: 3
      hba: 4
      rotatable_bonds: 1
      aromatic_rings: 1
      heavy_atom_count: 11
      lipinski_violations: 0
    mito_targeting:
      mechanism: carrier_mediated
      targeting_moiety: "none (pyrimidine nucleoside analog)"
      mito_accumulation_ratio: null
      evidence: "TK2 localized to mito matrix; substrate phosphorylation assumed"
      pmid: "19500277"
    scaffold:
      murcko_scaffold: "N1C(=O)C=CNC1=O"
      ring_system_count: 1
      contains_mito_privileged: false
      privileged_motif: "halopyrimidine"
    development:
      highest_phase: preclinical
      indication: "TK2 deficiency; mtDNA depletion syndrome (substrate bypass)"
      originator: "TK2 substrate SAR"
      patent_status: "active"
    seed_eligible: true
    fragment_decomposable: true
    novelty_baseline: false
    notes: "TK2 substrate-competition inhibitor. Fragment-like halopyrimidine. TK2 deficiency causes dTTP pool depletion → mtDNA depletion. Substrate bypass (dCyd/dThd supplementation) is current clinical approach. This compound represents a pharmacological probe for TK2 enzyme SAR."

  - compound_id: MITO_CPD_0091
    compound_name: "Deoxythymidine 5'-monophosphate (dTMP)"
    smiles: "Cc1cn([C@@H]2CC(OP(=O)(O)O)[C@@H](CO)O2)c(=O)[nH]1"
    inchi_key: "GYOZYWVXFNDGLU-XLPZGREQSA-N"
    molecular_formula: "C10H15N2O8P"
    molecular_weight: 322.21
    category: tool_compound
    source_db: ChEMBL
    source_id: CHEMBL1044
    pmid: ["25115384", "29636355"]
    target_ids: ["MITO_TGT_007", "MITO_TGT_018"]
    primary_target_id: MITO_TGT_007
    selectivity_profile: "TK2 product/POLG substrate; mito nucleotide pool reference; endogenous metabolite"
    bioactivity:
      - assay_type: biochemical
        endpoint: "Km (TK2 product)"
        value: 12000.0
        unit: "nM"
        conditions: "Recombinant hTK2; [3H]-thymidine phosphorylation product"
        pmid: "25115384"
    best_potency_nM: 12000.0
    physicochemical:
      logP: -2.4
      logD_7_4: -3.8
      tpsa: 168.1
      hbd: 3
      hba: 9
      rotatable_bonds: 5
      aromatic_rings: 1
      heavy_atom_count: 21
      lipinski_violations: 2
    mito_targeting:
      mechanism: carrier_mediated
      targeting_moiety: "none (nucleotide transporter)"
      mito_accumulation_ratio: null
      evidence: "TK2 substrate; mito dTTP pool precursor"
      pmid: "25115384"
    scaffold:
      murcko_scaffold: "c1cn(CCCC)c(=O)[nH]1"
      ring_system_count: 2
      contains_mito_privileged: false
      privileged_motif: "thymidine monophosphate"
    development:
      highest_phase: approved
      indication: "Endogenous metabolite; dTMP supplementation for TK2 deficiency"
      originator: "Endogenous"
      patent_status: "public_domain"
    seed_eligible: false
    fragment_decomposable: true
    novelty_baseline: true
    notes: "Endogenous TK2 phosphorylation product; POLG substrate precursor. Reference for dTTP pool restoration. Covers TK2-POLG axis jointly. High TPSA limits cell penetration as exogenous supplement — pro-drug strategies being developed. Included for TK2 target coverage."

  - compound_id: MITO_CPD_0092
    compound_name: "Mildronate (Meldonium)"
    smiles: "OC(=O)[N+](CC([N+](C)(C)C)=O)([O-])C"
    inchi_key: "QXZUUHYBWMWJHK-UHFFFAOYSA-N"
    molecular_formula: "C6H14N2O4"
    molecular_weight: 162.19
    category: approved_drug
    source_db: ChEMBL
    source_id: CHEMBL591711
    pmid: ["10587406", "27029477"]
    target_ids: ["MITO_TGT_006"]
    primary_target_id: MITO_TGT_006
    selectivity_profile: "Carnitine synthesis inhibitor; reduces long-chain FA import into mito; anti-ischemic"
    bioactivity:
      - assay_type: biochemical
        endpoint: "IC50 (gamma-butyrobetaine hydroxylase)"
        value: 62000.0
        unit: "nM"
        conditions: "Rat liver homogenate; gamma-BB hydroxylase; carnitine quantification"
        pmid: "10587406"
    best_potency_nM: 62000.0
    physicochemical:
      logP: -3.2
      logD_7_4: -3.8
      tpsa: 76.1
      hbd: 1
      hba: 4
      rotatable_bonds: 3
      aromatic_rings: 0
      heavy_atom_count: 12
      lipinski_violations: 0
    mito_targeting:
      mechanism: carrier_mediated
      targeting_moiety: "none (carnitine analog)"
      mito_accumulation_ratio: null
      evidence: "Reduces acylcarnitine mito import; shifts metabolism to glucose oxidation"
      pmid: "10587406"
    scaffold:
      murcko_scaffold: "OC(=O)N(OC)(C)CC(=O)"
      ring_system_count: 0
      contains_mito_privileged: false
      privileged_motif: "zwitterionic carnitine analog"
    development:
      highest_phase: approved
      indication: "Heart failure, angina (approved Russia/Latvia, Mildronate); anti-doping banned substance"
      originator: "Grindeks Latvia"
      patent_status: "active"
    seed_eligible: false
    fragment_decomposable: true
    novelty_baseline: true
    notes: "Carnitine competitive inhibitor. Reduces fatty acid import into mitochondria → increases glucose oxidation efficiency. Cardioprotective anti-ischemic mechanism. Banned by WADA 2016 (athletic performance). Covers SLC22A5 (OCTN2) carnitine transporter target (MITO_TGT_006). Reference for carnitine shuttle SAR."

  - compound_id: MITO_CPD_0093
    compound_name: "L-carnitine"
    smiles: "C[N+](C)(C)CC(CC([O-])=O)O"
    inchi_key: "PHIQHXFUZVPYII-ZCFIWIBFSA-N"
    molecular_formula: "C7H15NO3"
    molecular_weight: 161.20
    category: approved_drug
    source_db: ChEMBL
    source_id: CHEMBL803
    pmid: ["9291523", "23643782"]
    target_ids: ["MITO_TGT_006"]
    primary_target_id: MITO_TGT_006
    selectivity_profile: "OCTN2 substrate; mito fatty acid transport; SLC22A5 endogenous ligand"
    bioactivity:
      - assay_type: biochemical
        endpoint: "Km (SLC22A5/OCTN2)"
        value: 26000.0
        unit: "nM"
        conditions: "Oocyte expression; [3H]-L-carnitine uptake"
        pmid: "9291523"
    best_potency_nM: 26000.0
    physicochemical:
      logP: -3.8
      logD_7_4: -4.4
      tpsa: 76.1
      hbd: 1
      hba: 3
      rotatable_bonds: 4
      aromatic_rings: 0
      heavy_atom_count: 11
      lipinski_violations: 0
    mito_targeting:
      mechanism: carrier_mediated
      targeting_moiety: "none (OCTN2 substrate)"
      mito_accumulation_ratio: null
      evidence: "IMM carnitine-acylcarnitine translocase (CACT) shuttles acylcarnitines"
      pmid: "9291523"
    scaffold:
      murcko_scaffold: "C[N+](C)(C)CCCC([O-])=O"
      ring_system_count: 0
      contains_mito_privileged: false
      privileged_motif: "quaternary ammonium carnitine"
    development:
      highest_phase: approved
      indication: "Primary/secondary carnitine deficiency; dialysis-associated carnitine deficiency"
      originator: "Sigma-Tau (Carnitor)"
      patent_status: "generic"
    seed_eligible: false
    fragment_decomposable: true
    novelty_baseline: true
    notes: "Endogenous OCTN2 substrate. L-carnitine shuttles activated fatty acids into mito matrix. Approved for carnitine deficiency. SLC22A5 target (MITO_TGT_006). Reference compound for carnitine transporter pharmacophore. High TPSA, zwitterionic — not passively permeable."

  - compound_id: MITO_CPD_0094
    compound_name: "Compound A11 (AIFM1 dimerization inhibitor)"
    smiles: "O=C(Nc1ccc(C(=O)N2CCN(c3ccccc3)CC2)cc1)c1ccc(F)cc1"
    inchi_key: "MRPABNTMKJYQHJ-UHFFFAOYSA-N"
    molecular_formula: "C26H25FN4O2"
    molecular_weight: 460.50
    category: bioactive_hit
    source_db: PubChem
    source_id: "CID 91900281"
    pmid: ["32496188", "35194027"]
    target_ids: ["MITO_TGT_025"]
    primary_target_id: MITO_TGT_025
    selectivity_profile: "AIFM1 dimerization inhibitor; prevents pro-apoptotic large-scale DNA fragmentation"
    bioactivity:
      - assay_type: biochemical
        endpoint: "IC50 (AIFM1 dimerization)"
        value: 2800.0
        unit: "nM"
        conditions: "Recombinant hAIFM1; SPR competition assay"
        pmid: "32496188"
    best_potency_nM: 2800.0
    physicochemical:
      logP: 3.3
      logD_7_4: 2.9
      tpsa: 65.2
      hbd: 1
      hba: 4
      rotatable_bonds: 7
      aromatic_rings: 3
      heavy_atom_count: 33
      lipinski_violations: 0
    mito_targeting:
      mechanism: passive_diffusion
      targeting_moiety: "none"
      mito_accumulation_ratio: null
      evidence: "IMS AIFM1 target; cell-permeable; cyt c/AIFM1 release attenuated"
      pmid: "32496188"
    scaffold:
      murcko_scaffold: "O=C(Nc1ccccc1)c1ccc(C(=O)N2CCN(c3ccccc3)CC2)cc1"
      ring_system_count: 3
      contains_mito_privileged: false
      privileged_motif: "phenylpiperazine"
    development:
      highest_phase: preclinical
      indication: "Neurodegeneration (AIFM1-dependent caspase-independent apoptosis)"
      originator: "Academic SAR"
      patent_status: "pending"
    seed_eligible: true
    fragment_decomposable: true
    novelty_baseline: false
    notes: "AIFM1 dimerization inhibitor. 2.8 µM SPR IC50. AIFM1 nuclear translocation requires dimerization — blocking dimerization prevents large-scale DNA fragmentation in caspase-independent apoptosis. Phenylpiperazine-bis-amide scaffold. IMS target coverage."

  - compound_id: MITO_CPD_0095
    compound_name: "Compound 3 (PINK1 UBL substrate mimetic)"
    smiles: "O=C(Nc1ccnc(NC(=O)c2ccc(Cl)cc2)c1)C1CCCC1"
    inchi_key: "WANMPHNBPTHIKZ-UHFFFAOYSA-N"
    molecular_formula: "C18H19ClN4O2"
    molecular_weight: 374.82
    category: preclinical_lead
    source_db: PubChem
    source_id: "CID 71723861"
    pmid: ["34879232", "36543126"]
    target_ids: ["MITO_TGT_009", "MITO_TGT_010"]
    primary_target_id: MITO_TGT_009
    selectivity_profile: "PINK1 substrate-competitive; pyridyl diamide scaffold; dual PINK1-Parkin axis"
    bioactivity:
      - assay_type: cellular
        endpoint: "EC50 (mitophagy induction, PINK1-dependent)"
        value: 890.0
        unit: "nM"
        conditions: "SH-SY5Y; CCCP-independent LC3 puncta; PINK1 KO negative control"
        pmid: "34879232"
    best_potency_nM: 890.0
    physicochemical:
      logP: 2.4
      logD_7_4: 2.0
      tpsa: 72.0
      hbd: 2
      hba: 4
      rotatable_bonds: 5
      aromatic_rings: 2
      heavy_atom_count: 25
      lipinski_violations: 0
    mito_targeting:
      mechanism: passive_diffusion
      targeting_moiety: "none"
      mito_accumulation_ratio: null
      evidence: "OMM PINK1; cell-permeable neuronal target engagement"
      pmid: "34879232"
    scaffold:
      murcko_scaffold: "O=C(Nc1ccncc1NC(=O)C2CCCC2)c1ccccc1"
      ring_system_count: 3
      contains_mito_privileged: false
      privileged_motif: "pyridyl diamide"
    development:
      highest_phase: preclinical
      indication: "Parkinson disease (PINK1-Parkin mitophagy)"
      originator: "Bharat group"
      patent_status: "pending"
    seed_eligible: true
    fragment_decomposable: true
    novelty_baseline: false
    notes: "Sub-micromolar PINK1-dependent mitophagy inducer. Pyridyl bis-amide scaffold activates PINK1-Parkin pathway. Cyclopentyl cap + chlorobenzamide matches PINK1 UBL-binding subpocket. PINK1 and PRKN axis coverage. Neurodegeneration PD application."

  - compound_id: MITO_CPD_0096
    compound_name: "USP30 inhibitor MF-094"
    smiles: "O=C(Nc1cccc(C(=O)Nc2ccc(CN3CCS(=O)(=O)CC3)cc2)c1)Cc1ccccc1"
    inchi_key: "HDMZSGRZMBYKSG-UHFFFAOYSA-N"
    molecular_formula: "C27H30N4O4S"
    molecular_weight: 522.62
    category: preclinical_lead
    source_db: PubChem
    source_id: "CID 135398577"
    pmid: ["31831732", "34747731"]
    target_ids: ["MITO_TGT_010"]
    primary_target_id: MITO_TGT_010
    selectivity_profile: "USP30 deubiquitinase inhibitor; OMM-localized DUB; enhances PINK1-Parkin mitophagy"
    bioactivity:
      - assay_type: biochemical
        endpoint: "IC50 (USP30)"
        value: 180.0
        unit: "nM"
        conditions: "Recombinant hUSP30; Ub-AMC fluorescent substrate"
        pmid: "31831732"
    best_potency_nM: 180.0
    physicochemical:
      logP: 2.7
      logD_7_4: 2.3
      tpsa: 100.5
      hbd: 2
      hba: 6
      rotatable_bonds: 8
      aromatic_rings: 3
      heavy_atom_count: 36
      lipinski_violations: 0
    mito_targeting:
      mechanism: passive_diffusion
      targeting_moiety: "none"
      mito_accumulation_ratio: null
      evidence: "OMM USP30 target; mitophagy enhancement confirmed by LC3 and mtDNA clearance"
      pmid: "31831732"
    scaffold:
      murcko_scaffold: "O=C(Nc1ccccc1)Cc1ccccc1"
      ring_system_count: 3
      contains_mito_privileged: false
      privileged_motif: "piperazine sulfonyl"
    development:
      highest_phase: preclinical
      indication: "Parkinson disease; PINK1-Parkin axis enhancement via USP30 blockade"
      originator: "Mission Therapeutics"
      patent_status: "active"
    seed_eligible: true
    fragment_decomposable: true
    novelty_baseline: false
    notes: "USP30 deubiquitinase inhibitor. 180 nM IC50. USP30 is OMM-localized DUB that removes Parkin-added ubiquitin from mito — blocking USP30 amplifies PINK1-Parkin mitophagy signal. Key target for neurodegeneration. Mission Therapeutics clinical pipeline. Covers PRKN/PINK1 axis via USP30 substrate. OMM target."

  - compound_id: MITO_CPD_0097
    compound_name: "Compound 6 (TBK1/OPTN-p62 axis ULK1 activator)"
    smiles: "Cc1ccc(-c2nc3ccc(NC(=O)c4ccc(N5CCCC5)cc4)cc3[nH]2)cc1"
    inchi_key: "WVTNPNDSNXERQY-UHFFFAOYSA-N"
    molecular_formula: "C28H29N5O"
    molecular_weight: 467.57
    category: preclinical_lead
    source_db: PubChem
    source_id: "CID 91920851"
    pmid: ["33456568", "35218892"]
    target_ids: ["MITO_TGT_009"]
    primary_target_id: MITO_TGT_009
    selectivity_profile: "ULK1 kinase activator; downstream PINK1-Parkin mitophagy inducer; autophagy initiation"
    bioactivity:
      - assay_type: cellular
        endpoint: "EC50 (mitophagy induction)"
        value: 450.0
        unit: "nM"
        conditions: "HeLa; mt-Keima mitophagy reporter; 16h treatment"
        pmid: "33456568"
    best_potency_nM: 450.0
    physicochemical:
      logP: 4.1
      logD_7_4: 3.7
      tpsa: 62.4
      hbd: 1
      hba: 3
      rotatable_bonds: 5
      aromatic_rings: 4
      heavy_atom_count: 34
      lipinski_violations: 0
    mito_targeting:
      mechanism: passive_diffusion
      targeting_moiety: "none"
      mito_accumulation_ratio: null
      evidence: "Cytosolic/OMM-proximal ULK1 target; mito clearance confirmed"
      pmid: "33456568"
    scaffold:
      murcko_scaffold: "c1ccc(-c2nc3ccccc3[nH]2)cc1"
      ring_system_count: 3
      contains_mito_privileged: false
      privileged_motif: "aryl benzimidazole"
    development:
      highest_phase: preclinical
      indication: "Parkinson disease; alpha-synuclein clearance via mitophagy"
      originator: "HTS academic"
      patent_status: "pending"
    seed_eligible: true
    fragment_decomposable: true
    novelty_baseline: false
    notes: "ULK1-activating mitophagy inducer acting downstream of PINK1-Parkin. 450 nM mt-Keima EC50. Aryl-benzimidazole core activates ULK1-AMPK signaling. Relevant to PINK1 target coverage via ULK1-dependent mitophagy amplification."

  - compound_id: MITO_CPD_0098
    compound_name: "NAMPTi FK866 (mito NAD+ depletion tool)"
    smiles: "O=C(/C=C/c1ccncc1)Nc1ccc(CCCCn2cnc3ccccc32)cc1"
    inchi_key: "BWZVCCNYKMEVEX-WAYWQWQTSA-N"
    molecular_formula: "C26H25N5O"
    molecular_weight: 427.51
    category: tool_compound
    source_db: ChEMBL
    source_id: CHEMBL575526
    pmid: ["14613929", "25288803"]
    target_ids: ["MITO_TGT_020"]
    primary_target_id: MITO_TGT_020
    selectivity_profile: "NAMPT inhibitor; depletes NAD+ pool → SIRT1-3 inactivation → TFAM de-regulation"
    bioactivity:
      - assay_type: biochemical
        endpoint: "IC50 (NAMPT)"
        value: 0.4
        unit: "nM"
        conditions: "Recombinant hNAMPT; [14C]-NMN formation assay"
        pmid: "14613929"
    best_potency_nM: 0.4
    physicochemical:
      logP: 4.5
      logD_7_4: 4.1
      tpsa: 62.5
      hbd: 1
      hba: 4
      rotatable_bonds: 8
      aromatic_rings: 3
      heavy_atom_count: 32
      lipinski_violations: 0
    mito_targeting:
      mechanism: passive_diffusion
      targeting_moiety: "none"
      mito_accumulation_ratio: null
      evidence: "Cytosolic NAMPT; mito NAD+ depletion indirect; SIRT3 inactivation confirmed"
      pmid: "25288803"
    scaffold:
      murcko_scaffold: "O=C(/C=C/c1ccncc1)Nc1ccccc1"
      ring_system_count: 3
      contains_mito_privileged: false
      privileged_motif: "pyridyl styryl amide"
    development:
      highest_phase: phase2
      indication: "Cancer (metabolic targeting); Phase II lymphoma"
      originator: "Astellas/TopoTarget"
      patent_status: "active"
    seed_eligible: false
    fragment_decomposable: true
    novelty_baseline: false
    notes: "Sub-picomolar NAMPT inhibitor. Depletes cellular NAD+ → SIRT1/2/3 inactivation → TFAM hyperacetylation → mtDNA transcription reduction. Tool for NAD+-dependent mito regulation. Cancer application. Not mito-enhancing — included as TFAM axis negative control reference."

  - compound_id: MITO_CPD_0099
    compound_name: "Compound 5 (MRPS27 translation disruptor)"
    smiles: "O=C(Nc1cc(-c2ccncc2)ccc1F)c1cccc2ccccc12"
    inchi_key: "KXZIFWLPJPQSLH-UHFFFAOYSA-N"
    molecular_formula: "C23H17FN2O"
    molecular_weight: 360.39
    category: bioactive_hit
    source_db: PubChem
    source_id: "CID 91921803"
    pmid: ["34453886", "35837190"]
    target_ids: ["MITO_TGT_024"]
    primary_target_id: MITO_TGT_024
    selectivity_profile: "Mito ribosome small subunit (28S) binding; inhibits OXPHOS complex translation"
    bioactivity:
      - assay_type: cellular
        endpoint: "IC50 (mito translation)"
        value: 2200.0
        unit: "nM"
        conditions: "HEK293T; [35S]-Met mito protein labeling; Chase 6h"
        pmid: "34453886"
    best_potency_nM: 2200.0
    physicochemical:
      logP: 4.3
      logD_7_4: 3.9
      tpsa: 42.7
      hbd: 1
      hba: 2
      rotatable_bonds: 4
      aromatic_rings: 4
      heavy_atom_count: 27
      lipinski_violations: 0
    mito_targeting:
      mechanism: passive_diffusion
      targeting_moiety: "none"
      mito_accumulation_ratio: null
      evidence: "Mito matrix ribosome target; 35S-Met labeling reduction confirmed"
      pmid: "34453886"
    scaffold:
      murcko_scaffold: "O=C(Nc1ccccc1)c1cccc2ccccc12"
      ring_system_count: 3
      contains_mito_privileged: false
      privileged_motif: "naphthamide"
    development:
      highest_phase: preclinical
      indication: "Cancer (mito translation dependency); OXPHOS-dependent tumors"
      originator: "HTS phenotypic"
      patent_status: "pending"
    seed_eligible: true
    fragment_decomposable: true
    novelty_baseline: false
    notes: "Mito ribosome translation inhibitor. 2.2 µM cellular IC50. Targets 28S mitoribosome small subunit. Inhibits synthesis of MT-encoded OXPHOS subunits (ND1-6, COX1-3, ATP6/8, Cyt b). Cancer application: mito translation-dependent tumors. Covers mito ribosome target (MITO_TGT_024)."

  - compound_id: MITO_CPD_0100
    compound_name: "Tigecycline"
    smiles: 'CN(C)c1ccc2c(c1)C(=O)C1(O)C(=O)/C(=C\NC(=O)CNC(C)(C)C)C(=O)c3c(N(C)C)cccc3C1=C2O'
    inchi_key: "FPIFAZPCNPMJTH-DMTCNVIQSA-N"
    molecular_formula: "C29H39N5O8"
    molecular_weight: 585.65
    category: approved_drug
    source_db: ChEMBL
    source_id: CHEMBL136100
    pmid: ["23022210", "25945594"]
    target_ids: ["MITO_TGT_024"]
    primary_target_id: MITO_TGT_024
    selectivity_profile: "Glycylcycline antibiotic; mito ribosome (55S) inhibitor; inhibits OXPHOS complex translation"
    bioactivity:
      - assay_type: cellular
        endpoint: "IC50 (AML cell viability via mito translation)"
        value: 3000.0
        unit: "nM"
        conditions: "AML stem cells; 48h; validated by 35S-Met mito labeling"
        pmid: "23022210"
    best_potency_nM: 3000.0
    physicochemical:
      logP: 0.1
      logD_7_4: -0.4
      tpsa: 212.9
      hbd: 6
      hba: 10
      rotatable_bonds: 6
      aromatic_rings: 3
      heavy_atom_count: 41
      lipinski_violations: 3
    mito_targeting:
      mechanism: passive_diffusion
      targeting_moiety: "none (broad tetracycline penetration)"
      mito_accumulation_ratio: 5.0
      evidence: "Mito ribosome binding confirmed by 35S-Met assay; mito-selective over cytosolic ribosomes"
      pmid: "25945594"
    scaffold:
      murcko_scaffold: "O=C1c2ccccc2C(=O)C1(O)C(=O)"
      ring_system_count: 3
      contains_mito_privileged: false
      privileged_motif: "tetracycline"
    development:
      highest_phase: approved
      indication: "Complicated infections (Tygacil); cancer repurposing (leukemia stem cells)"
      originator: "Wyeth/Pfizer"
      patent_status: "active"
    seed_eligible: false
    fragment_decomposable: false
    novelty_baseline: true
    notes: "Broad-spectrum antibiotic repurposed as mito translation inhibitor in cancer. Preferentially inhibits mito 55S ribosome vs cytosolic 80S. AML leukemic stem cell selectivity. Very high TPSA limits bioavailability improvements. Included for mito ribosome target coverage (MITO_TGT_024) and as approved drug comparator."

  # ============================================================
  # CATEGORY: TOOL COMPOUNDS / BIOACTIVE HITS (entries 0101–0130)
  # ============================================================

  - compound_id: MITO_CPD_0101
    compound_name: "Compound 8 (COQ2 prenyl-binding inhibitor)"
    smiles: "O=C(Nc1ccc(OC)cc1)c1ccc(Br)cc1"
    inchi_key: "GKIUWZZCMKRNOY-UHFFFAOYSA-N"
    molecular_formula: "C14H12BrNO2"
    molecular_weight: 334.16
    category: bioactive_hit
    source_db: PubChem
    source_id: "CID 2760690"
    pmid: ["28489526", "31072631"]
    target_ids: ["MITO_TGT_016"]
    primary_target_id: MITO_TGT_016
    selectivity_profile: "COQ2 prenyl-binding pocket hit; 4-bromobenzoate amide; IMM CoQ10 biosynthesis"
    bioactivity:
      - assay_type: biochemical
        endpoint: "IC50 (COQ2 prenylation)"
        value: 15000.0
        unit: "nM"
        conditions: "Recombinant Saccharomyces cerevisiae Coq2; HPLC prenylation assay"
        pmid: "28489526"
    best_potency_nM: 15000.0
    physicochemical:
      logP: 3.5
      logD_7_4: 3.1
      tpsa: 38.2
      hbd: 1
      hba: 2
      rotatable_bonds: 4
      aromatic_rings: 2
      heavy_atom_count: 18
      lipinski_violations: 0
    mito_targeting:
      mechanism: passive_diffusion
      targeting_moiety: "none"
      mito_accumulation_ratio: null
      evidence: "IMM-embedded COQ2 target; lipophilic substrate"
      pmid: "28489526"
    scaffold:
      murcko_scaffold: "O=C(Nc1ccccc1)c1ccccc1"
      ring_system_count: 2
      contains_mito_privileged: false
      privileged_motif: "benzamide"
    development:
      highest_phase: preclinical
      indication: "CoQ10 deficiency; mito disease"
      originator: "Fragment SAR"
      patent_status: "pending"
    seed_eligible: true
    fragment_decomposable: true
    novelty_baseline: false
    notes: "4-Bromobenzoate amide COQ2 inhibitor. IMM-embedded target. Para-bromo phenyl extends into prenyl binding channel. Anisidine amide nitrogen contacts Lys211. 15 µM IC50 — lead-like fragment. Key starting point for COQ2 prenyl pocket SAR with goal of enzyme activation for CoQ10 restoration."

  - compound_id: MITO_CPD_0102
    compound_name: "2,4-Dinitrophenol (DNP)"
    smiles: "Oc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]"
    inchi_key: "JEVVKJMRZMXFBT-UHFFFAOYSA-N"
    molecular_formula: "C6H4N2O5"
    molecular_weight: 184.11
    category: tool_compound
    source_db: ChEMBL
    source_id: CHEMBL14583
    pmid: ["14907713", "9343448"]
    target_ids: ["MITO_TGT_005"]
    primary_target_id: MITO_TGT_005
    selectivity_profile: "Protonophore uncoupler; classical mito membrane potential disruptor; assay calibration control"
    bioactivity:
      - assay_type: functional
        endpoint: "EC50 (ΔΨm collapse)"
        value: 50000.0
        unit: "nM"
        conditions: "Isolated rat liver mito; JC-1 fluorescence"
        pmid: "14907713"
    best_potency_nM: 50000.0
    physicochemical:
      logP: 1.9
      logD_7_4: -0.2
      tpsa: 107.7
      hbd: 1
      hba: 5
      rotatable_bonds: 1
      aromatic_rings: 1
      heavy_atom_count: 13
      lipinski_violations: 0
    mito_targeting:
      mechanism: passive_diffusion
      targeting_moiety: "none (protonophore)"
      mito_accumulation_ratio: 1.0
      evidence: "Distributes across all membranes; proton cycling"
      pmid: "14907713"
    scaffold:
      murcko_scaffold: "c1ccc(O)cc1"
      ring_system_count: 1
      contains_mito_privileged: false
      privileged_motif: "dinitrophenol"
    development:
      highest_phase: tool_only
      indication: "Research tool; TOXIC — not therapeutic"
      originator: "Classical biochemistry (weight loss drug, historical)"
      patent_status: "public_domain"
    seed_eligible: false
    fragment_decomposable: false
    novelty_baseline: true
    notes: "Classical protonophore. TOXIC — banned for human use (numerous deaths from hyperthermia). Used only as biochemical tool for uncoupling assays. Calibration reference for Seahorse and JC-1 ΔΨm measurements. Not therapeutic. ΔΨm-disruption negative control."

  - compound_id: MITO_CPD_0103
    compound_name: "Tamoxifen"
    smiles: "C(/C(=C/CCN(C)C)c1ccccc1)=C/c1ccc(OCC)cc1"
    inchi_key: "NKANXQFJJICGDU-QPLCGJKRSA-N"
    molecular_formula: "C26H29NO"
    molecular_weight: 371.51
    category: approved_drug
    source_db: ChEMBL
    source_id: CHEMBL83
    pmid: ["12629070", "23022210"]
    target_ids: ["MITO_TGT_001", "MITO_TGT_015"]
    primary_target_id: MITO_TGT_001
    selectivity_profile: "SERM; secondary Complex I inhibitor; cardiotoxicity mito mechanism"
    bioactivity:
      - assay_type: biochemical
        endpoint: "IC50 (Complex I)"
        value: 7800.0
        unit: "nM"
        conditions: "Rat heart mito; NADH oxidase"
        pmid: "12629070"
    best_potency_nM: 7800.0
    physicochemical:
      logP: 6.3
      logD_7_4: 6.0
      tpsa: 12.5
      hbd: 0
      hba: 1
      rotatable_bonds: 6
      aromatic_rings: 3
      heavy_atom_count: 28
      lipinski_violations: 1
    mito_targeting:
      mechanism: passive_diffusion
      targeting_moiety: "none"
      mito_accumulation_ratio: 3.5
      evidence: "Lipophilic SERM; mito CI inhibition confirmed in isolated preparations"
      pmid: "12629070"
    scaffold:
      murcko_scaffold: "c1ccc(/C=C/c2ccccc2)cc1"
      ring_system_count: 3
      contains_mito_privileged: false
      privileged_motif: "stilbene triphenylene"
    development:
      highest_phase: approved
      indication: "Breast cancer (ER+ SERM)"
      originator: "ICI (AstraZeneca)"
      patent_status: "generic"
    seed_eligible: false
    fragment_decomposable: false
    novelty_baseline: false
    notes: "Approved SERM with secondary CI inhibitory activity. CI inhibition contributes to tamoxifen cardiotoxicity. Included for CI target coverage (MITO_TGT_001) and as approved drug pharmacology reference. Not seed-eligible — SERM activity not relevant to mito program."

  - compound_id: MITO_CPD_0104
    compound_name: "Compound 4b (SDHA cancer therapeutic)"
    smiles: "O=C(Nc1ccc2c(c1)OCCO2)c1ccc(Cl)c(Cl)c1"
    inchi_key: "YJLFLXQMCXAOLR-UHFFFAOYSA-N"
    molecular_formula: "C15H13Cl2NO3"
    molecular_weight: 346.18
    category: preclinical_lead
    source_db: PubChem
    source_id: "CID 44283913"
    pmid: ["30392752", "34281873"]
    target_ids: ["MITO_TGT_004"]
    primary_target_id: MITO_TGT_004
    selectivity_profile: "SDHA Q-site inhibitor; dichlorobenzamide benzo-dioxan scaffold; SDH-mutant tumor context"
    bioactivity:
      - assay_type: biochemical
        endpoint: "IC50 (Complex II)"
        value: 340.0
        unit: "nM"
        conditions: "Porcine heart SMP; succinate-CoQ reductase"
        pmid: "30392752"
    best_potency_nM: 340.0
    physicochemical:
      logP: 3.1
      logD_7_4: 2.7
      tpsa: 52.6
      hbd: 1
      hba: 3
      rotatable_bonds: 4
      aromatic_rings: 2
      heavy_atom_count: 22
      lipinski_violations: 0
    mito_targeting:
      mechanism: passive_diffusion
      targeting_moiety: "none"
      mito_accumulation_ratio: 4.8
      evidence: "Mito enrichment by fractionation; CII-specific NADH oxidase assay"
      pmid: "30392752"
    scaffold:
      murcko_scaffold: "O=C(Nc1ccc2c(c1)OCCO2)c1ccccc1"
      ring_system_count: 3
      contains_mito_privileged: false
      privileged_motif: "dichlorobenzamide benzo-dioxane"
    development:
      highest_phase: preclinical
      indication: "SDH-mutant paraganglioma; SDHA-mutant GI stromal tumor"
      originator: "Medicinal chemistry SAR"
      patent_status: "pending"
    seed_eligible: true
    fragment_decomposable: true
    novelty_baseline: false
    notes: "340 nM Complex II inhibitor. Benzo-1,4-dioxan amine extension improves CII selectivity. Relates to Atpenin A5 pharmacophore but smaller, more drug-like. Key for SDHA SAR evolution."

  - compound_id: MITO_CPD_0105
    compound_name: "Dimethyl fumarate (DMF)"
    smiles: "COC(=O)/C=C/C(=O)OC"
    inchi_key: "LDCRTTXIJACKKU-ONEGZZNKSA-N"
    molecular_formula: "C6H8O4"
    molecular_weight: 144.12
    category: approved_drug
    source_db: ChEMBL
    source_id: CHEMBL1370"
    pmid: ["18818301", "25018023"]
    target_ids: ["MITO_TGT_021"]
    primary_target_id: MITO_TGT_021
    selectivity_profile: "Nrf2/LONP1 activator; electrophilic alkylating agent; KEAP1 Cys151/273/288 modification"
    bioactivity:
      - assay_type: cellular
        endpoint: "EC50 (Nrf2 nuclear translocation)"
        value: 12000.0
        unit: "nM"
        conditions: "HEK293; Nrf2-luciferase reporter; 6h"
        pmid: "18818301"
    best_potency_nM: 12000.0
    physicochemical:
      logP: 0.5
      logD_7_4: 0.2
      tpsa: 52.6
      hbd: 0
      hba: 4
      rotatable_bonds: 4
      aromatic_rings: 0
      heavy_atom_count: 10
      lipinski_violations: 0
    mito_targeting:
      mechanism: passive_diffusion
      targeting_moiety: "none"
      mito_accumulation_ratio: 2.0
      evidence: "Mito Cys alkylation confirmed by mass spec; mito LONP1 activation secondary"
      pmid: "18818301"
    scaffold:
      murcko_scaffold: "COC(=O)C=CC(=O)OC"
      ring_system_count: 0
      contains_mito_privileged: false
      privileged_motif: "Michael acceptor fumarate"
    development:
      highest_phase: approved
      indication: "Multiple sclerosis (Tecfidera/Skilarence); psoriasis"
      originator: "Biogen"
      patent_status: "active"
    seed_eligible: false
    fragment_decomposable: true
    novelty_baseline: false
    notes: "Approved MS drug. Nrf2 pathway activator via KEAP1 Cys modification (Michael addition). Secondary LONP1 activation via Nrf2-mediated transcription. Fumarate ester prodrug (mono-methyl fumarate active). Not seed-eligible — mito effect secondary. LONP1/Nrf2 axis coverage."

  - compound_id: MITO_CPD_0106
    compound_name: "Sulforaphane"
    smiles: "C(CCCS(=O)=O)CC=S(=O)=O"
    inchi_key: "ATUOYWHBWRKTHZ-UHFFFAOYSA-N"
    molecular_formula: "C6H11NOS2"
    molecular_weight: 177.28
    category: bioactive_hit
    source_db: ChEMBL
    source_id: CHEMBL1367
    pmid: ["11606625", "24382372"]
    target_ids: ["MITO_TGT_021"]
    primary_target_id: MITO_TGT_021
    selectivity_profile: "Isothiocyanate Nrf2/KEAP1 activator; electrophilic warhead; indirect LONP1 pathway"
    bioactivity:
      - assay_type: cellular
        endpoint: "EC50 (Nrf2 activation)"
        value: 3500.0
        unit: "nM"
        conditions: "Hepa1c1c7 cells; ARE-luciferase reporter"
        pmid: "11606625"
    best_potency_nM: 3500.0
    physicochemical:
      logP: 0.9
      logD_7_4: 0.6
      tpsa: 77.4
      hbd: 0
      hba: 3
      rotatable_bonds: 5
      aromatic_rings: 0
      heavy_atom_count: 10
      lipinski_violations: 0
    mito_targeting:
      mechanism: passive_diffusion
      targeting_moiety: "none"
      mito_accumulation_ratio: 2.5
      evidence: "Mito Cys modification confirmed; Nrf2 activation reduces mito ROS"
      pmid: "11606625"
    scaffold:
      murcko_scaffold: "CCCS(=O)=O"
      ring_system_count: 0
      contains_mito_privileged: false
      privileged_motif: "isothiocyanate"
    development:
      highest_phase: phase2
      indication: "Cancer chemopreventive; autism (Phase II); Nrf2 modulation"
      originator: "Natural product (broccoli)"
      patent_status: "public_domain"
    seed_eligible: false
    fragment_decomposable: true
    novelty_baseline: false
    notes: "Broccoli natural product isothiocyanate. Nrf2 activator via KEAP1 Cys modification. Phase II for multiple indications. Fragment-like, but electrophilic warhead (isothiocyanate) not ideal for selective LONP1 targeting. Useful as KEAP1-Nrf2 reference compound for LONP1 axis."

  - compound_id: MITO_CPD_0107
    compound_name: "Omaveloxolone"
    smiles: "O=C1OC2(C)CC[C@@]3(C)[C@@H](CC[C@H]4[C@@]3(C)CC(=O)c3c(C#N)c(=O)c(C=O)c(C)c34)C2=C1C"
    inchi_key: "LBDSXVIYZYSRII-HQMMCQRPSA-N"
    molecular_formula: "C32H41NO4"
    molecular_weight: 519.68
    category: approved_drug
    source_db: ChEMBL
    source_id: CHEMBL4523002
    pmid: ["29272213", "34879127"]
    target_ids: ["MITO_TGT_021"]
    primary_target_id: MITO_TGT_021
    selectivity_profile: "Nrf2 activator (CDDO class); Friedreich ataxia; LONP1 pathway activation"
    bioactivity:
      - assay_type: cellular
        endpoint: "EC50 (Nrf2 activation)"
        value: 16.0
        unit: "nM"
        conditions: "HEK293 Nrf2-reporter; 6h"
        pmid: "29272213"
    best_potency_nM: 16.0
    physicochemical:
      logP: 5.4
      logD_7_4: 5.0
      tpsa: 96.2
      hbd: 0
      hba: 4
      rotatable_bonds: 3
      aromatic_rings: 0
      heavy_atom_count: 37
      lipinski_violations: 1
    mito_targeting:
      mechanism: passive_diffusion
      targeting_moiety: "none (triterpenoid)"
      mito_accumulation_ratio: 6.8
      evidence: "Lipophilic triterpenoid; mito enrichment by fractionation"
      pmid: "29272213"
    scaffold:
      murcko_scaffold: "C1CCC2(CC1)CCCC2"
      ring_system_count: 4
      contains_mito_privileged: false
      privileged_motif: "triterpenoid"
    development:
      highest_phase: approved
      indication: "Friedreich ataxia (Skyclarys, FDA 2023)"
      originator: "Reata Pharmaceuticals"
      patent_status: "active"
    seed_eligible: true
    fragment_decomposable: false
    novelty_baseline: true
    notes: "FDA-approved Friedreich ataxia drug (2023). CDDO-Me analog. 16 nM Nrf2 activation. First approved mitochondrial disease drug from Nrf2/LONP1 pathway. Key approved benchmark for LONP1/Nrf2 program. Triterpenoid scaffold — not fragment-evolvable but important LONP1 pathway benchmark."

  - compound_id: MITO_CPD_0108
    compound_name: "CPI-613 (Devimistat)"
    smiles: "CC(C)(C)Nc1ccc(NC(=O)c2csc(Cc3ccccc3)n2)cc1"
    inchi_key: "SNDPXSYFESPGGJ-UHFFFAOYSA-N"
    molecular_formula: "C22H25N3O2S"
    molecular_weight: 411.52
    category: clinical_candidate
    source_db: ChEMBL
    source_id: CHEMBL3707231
    pmid: ["22344300", "32361005"]
    target_ids: ["MITO_TGT_001", "MITO_TGT_002"]
    primary_target_id: MITO_TGT_001
    selectivity_profile: "Lipoate analog; inhibits PDH/alpha-KGDH; disrupts mito TCA cycle at lipoate-dependent enzymes"
    bioactivity:
      - assay_type: cellular
        endpoint: "IC50 (AML cell viability)"
        value: 1200.0
        unit: "nM"
        conditions: "AML cell lines; 72h; Seahorse OCR reduction confirmed"
        pmid: "22344300"
    best_potency_nM: 1200.0
    physicochemical:
      logP: 4.2
      logD_7_4: 3.8
      tpsa: 72.1
      hbd: 2
      hba: 4
      rotatable_bonds: 6
      aromatic_rings: 2
      heavy_atom_count: 28
      lipinski_violations: 0
    mito_targeting:
      mechanism: passive_diffusion
      targeting_moiety: "none"
      mito_accumulation_ratio: null
      evidence: "Mito matrix TCA enzyme targets; cell-permeable confirmed"
      pmid: "22344300"
    scaffold:
      murcko_scaffold: "c1ccc(Cc2nc(NC(=O)c3cccnc3)cs2)cc1"
      ring_system_count: 3
      contains_mito_privileged: false
      privileged_motif: "thiazole"
    development:
      highest_phase: phase3
      indication: "AML (Phase III); PDAC (Phase II)"
      originator: "Cornerstone Pharmaceuticals"
      patent_status: "active"
    seed_eligible: true
    fragment_decomposable: true
    novelty_baseline: true
    notes: "Lipoate analog disrupting PDH and alpha-ketoglutarate dehydrogenase. Exploits cancer cell OXPHOS dependency. Phase III AML. Thiazole-anilide scaffold. Relevant to CI/CII target coverage (MITO_TGT_001/002) via TCA cycle substrate disruption."

  - compound_id: MITO_CPD_0109
    compound_name: "MitoSOX Red"
    smiles: "C[N+]1(CCCCC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c2cc3c(cc2CC1)cc1ccc(N)cc1c3=O"
    inchi_key: "RLBIQVVOMOPOHC-UHFFFAOYSA-O"
    molecular_formula: "C46H51N2OP2+"
    molecular_weight: 759.87
    category: mito_targeted_probe
    source_db: Thermo Fisher
    source_id: "M36008"
    pmid: ["20813050", "28920069"]
    target_ids: ["MITO_TGT_015"]
    primary_target_id: MITO_TGT_015
    selectivity_profile: "Mito superoxide indicator; TPP+-tethered hydroethidine; fluorescent ROS probe"
    bioactivity:
      - assay_type: functional
        endpoint: "Detection limit (mito superoxide)"
        value: 10.0
        unit: "nM"
        conditions: "Live cells; confocal imaging; 510 nm excitation/590 nm emission"
        pmid: "20813050"
    best_potency_nM: 10.0
    physicochemical:
      logP: 5.2
      logD_7_4: 4.9
      tpsa: 38.2
      hbd: 2
      hba: 2
      rotatable_bonds: 8
      aromatic_rings: 5
      heavy_atom_count: 49
      lipinski_violations: 2
    mito_targeting:
      mechanism: delphi_psi_driven
      targeting_moiety: "triphenylphosphonium (TPP+)"
      mito_accumulation_ratio: 1000.0
      evidence: "TPP+-driven mito accumulation; superoxide-specific 2-hydroxyethidium product"
      pmid: "20813050"
    scaffold:
      murcko_scaffold: "c1cccc2nc3ccc(N)cc3cc12"
      ring_system_count: 5
      contains_mito_privileged: true
      privileged_motif: "triphenylphosphonium (TPP+)"
    development:
      highest_phase: tool_only
      indication: "Research fluorescent probe; mito ROS imaging"
      originator: "Invitrogen/Thermo Fisher"
      patent_status: "active"
    seed_eligible: false
    fragment_decomposable: false
    novelty_baseline: true
    notes: "Gold-standard mito superoxide fluorescent probe. TPP+-driven 1000x mito accumulation. Hydroethidine reacts with superoxide to produce 2-hydroxyethidium (distinguishable from nonspecific oxidation). Standard in OXPHOS complex ROS assays. Research tool only."

  - compound_id: MITO_CPD_0110
    compound_name: "JC-1"
    smiles: "C(/C=C/c1ccc2c(c1)[n+](C)c1ccc3c(c1-2)CCCC3)=C/c1ccc2c(c1)N(C)c1ccc3c(c1-2)CCCC3"
    inchi_key: "ZJUXFBZLTCEFBH-IVMDWMLBSA-N"
    molecular_formula: "C25H27N2+"
    molecular_weight: 371.50
    category: mito_targeted_probe
    source_db: Sigma-Aldrich
    source_id: "T4069"
    pmid: ["14907713", "25018023"]
    target_ids: ["MITO_TGT_015"]
    primary_target_id: MITO_TGT_015
    selectivity_profile: "ΔΨm indicator dye; J-aggregate formation at polarized mito; green monomer/red aggregate ratio"
    bioactivity:
      - assay_type: functional
        endpoint: "EC50 (ΔΨm detection)"
        value: 1000.0
        unit: "nM"
        conditions: "Intact cells; flow cytometry; 530/590 ratio"
        pmid: "14907713"
    best_potency_nM: 1000.0
    physicochemical:
      logP: 4.1
      logD_7_4: 3.8
      tpsa: 7.1
      hbd: 0
      hba: 2
      rotatable_bonds: 5
      aromatic_rings: 4
      heavy_atom_count: 27
      lipinski_violations: 1
    mito_targeting:
      mechanism: delphi_psi_driven
      targeting_moiety: "cationic cyanine dye (intrinsic)"
      mito_accumulation_ratio: 500.0
      evidence: "ΔΨm-dependent J-aggregate formation; gold-standard mito potential assay"
      pmid: "14907713"
    scaffold:
      murcko_scaffold: "c1ccc2c(c1)N(C)c1ccc3c(c1-2)CCCC3"
      ring_system_count: 2
      contains_mito_privileged: false
      privileged_motif: "cyanine dye"
    development:
      highest_phase: tool_only
      indication: "Research fluorescent probe; ΔΨm assay"
      originator: "Multiple suppliers"
      patent_status: "public_domain"
    seed_eligible: false
    fragment_decomposable: false
    novelty_baseline: true
    notes: "Standard ΔΨm fluorescent indicator. Cationic cyanine accumulates in mito in proportion to ΔΨm. J-aggregates (red) form at high ΔΨm; monomers (green) at low/depolarized. Used universally to confirm mito targeting and assess compound effects on membrane potential. Assay calibration reference."

  - compound_id: MITO_CPD_0111
    compound_name: "Compound 7c (CLPP allosteric agonist)"
    smiles: "Clc1ccc2nc(N3CC(F)(F)C3)nc2c1"
    inchi_key: "VIFCFXZXHCRTRQ-UHFFFAOYSA-N"
    molecular_formula: "C12H12ClF2N4"
    molecular_weight: 304.72
    category: preclinical_lead
    source_db: PubChem
    source_id: "CID 135399127"
    pmid: ["33239434", "35847213"]
    target_ids: ["MITO_TGT_022"]
    primary_target_id: MITO_TGT_022
    selectivity_profile: "Truncated imipridone; ClpP agonist; difluorinated azetidine scaffold; improved CNS penetration"
    bioactivity:
      - assay_type: biochemical
        endpoint: "EC50 (ClpP activation)"
        value: 620.0
        unit: "nM"
        conditions: "Recombinant hClpP; FITC-casein degradation fluorescence"
        pmid: "33239434"
    best_potency_nM: 620.0
    physicochemical:
      logP: 2.3
      logD_7_4: 1.9
      tpsa: 43.8
      hbd: 0
      hba: 4
      rotatable_bonds: 2
      aromatic_rings: 2
      heavy_atom_count: 19
      lipinski_violations: 0
    mito_targeting:
      mechanism: passive_diffusion
      targeting_moiety: "none"
      mito_accumulation_ratio: 8.5
      evidence: "Mito matrix ClpP target; mito membrane potential-driven accumulation"
      pmid: "33239434"
    scaffold:
      murcko_scaffold: "c1cnc2ccccc2n1"
      ring_system_count: 2
      contains_mito_privileged: false
      privileged_motif: "imipridone fragment"
    development:
      highest_phase: preclinical
      indication: "AML; brain tumors (CNS penetration)"
      originator: "Medicinal chemistry"
      patent_status: "active"
    seed_eligible: true
    fragment_decomposable: true
    novelty_baseline: true
    notes: "Simplified imipridone with difluoroazetidine replacing piperazine. 620 nM ClpP activation EC50. Lower MW and improved CNS penetration vs ONC201. Chloro-diamine-pyrimidine scaffold. Key for ClpP agonist scaffold diversification SAR."

  - compound_id: MITO_CPD_0112
    compound_name: "Meclizine"
    smiles: "Clc1ccc(C(c2ccccc2)N2CCN(Cc3cnccn3)CC2)cc1"
    inchi_key: "YCCILVSKPBXVIP-UHFFFAOYSA-N"
    molecular_formula: "C25H27ClN4"
    molecular_weight: 390.91
    category: approved_drug
    source_db: ChEMBL
    source_id: CHEMBL511
    pmid: ["24336178", "27580060"]
    target_ids: ["MITO_TGT_001", "MITO_TGT_005"]
    primary_target_id: MITO_TGT_005
    selectivity_profile: "H1 antihistamine; Complex I/V modulator; PGC-1alpha mitobiogenesis activation"
    bioactivity:
      - assay_type: cellular
        endpoint: "EC50 (OCR increase, mito biogenesis)"
        value: 8000.0
        unit: "nM"
        conditions: "Primary hepatocytes; Seahorse XF; 24h pretreatment"
        pmid: "24336178"
    best_potency_nM: 8000.0
    physicochemical:
      logP: 4.5
      logD_7_4: 4.1
      tpsa: 19.0
      hbd: 0
      hba: 4
      rotatable_bonds: 5
      aromatic_rings: 3
      heavy_atom_count: 30
      lipinski_violations: 0
    mito_targeting:
      mechanism: passive_diffusion
      targeting_moiety: "none"
      mito_accumulation_ratio: 3.0
      evidence: "PGC-1alpha activation confirmed; OCR increase; mito biogenesis markers"
      pmid: "24336178"
    scaffold:
      murcko_scaffold: "c1ccc(CN2CCN(C(c3ccccc3)c3ccccc3)CC2)cc1"
      ring_system_count: 3
      contains_mito_privileged: false
      privileged_motif: "piperazine"
    development:
      highest_phase: approved
      indication: "Motion sickness (Antivert); repurposing for mito disease"
      originator: "Pfizer"
      patent_status: "generic"
    seed_eligible: false
    fragment_decomposable: true
    novelty_baseline: false
    notes: "FDA-approved antihistamine with secondary mito biogenesis activity. PGC-1alpha activation → TFAM/NRF1/OXPHOS upregulation. Repurposing study confirmed OCR increase. Not selective — H1 antihistamine activity dominates. Included for ComplexV/biogenesis coverage."

  - compound_id: MITO_CPD_0113
    compound_name: "Alpha-lipoic acid (ALA)"
    smiles: "OC(=O)CCCCC1CCSS1"
    inchi_key: "AGBQKNBQESQNJD-UHFFFAOYSA-N"
    molecular_formula: "C8H14O2S2"
    molecular_weight: 206.33
    category: approved_drug
    source_db: ChEMBL
    source_id: CHEMBL1108"
    pmid: ["16259909", "22251927"]
    target_ids: ["MITO_TGT_015", "MITO_TGT_001"]
    primary_target_id: MITO_TGT_015
    selectivity_profile: "Mito antioxidant cofactor; PDH/alpha-KGDH prosthetic group; endogenous lipoate"
    bioactivity:
      - assay_type: cellular
        endpoint: "EC50 (GSH replenishment)"
        value: 50000.0
        unit: "nM"
        conditions: "PC12 cells; paraquat oxidative stress; GSH quantification"
        pmid: "16259909"
    best_potency_nM: 50000.0
    physicochemical:
      logP: 1.9
      logD_7_4: 0.5
      tpsa: 80.5
      hbd: 1
      hba: 2
      rotatable_bonds: 5
      aromatic_rings: 0
      heavy_atom_count: 12
      lipinski_violations: 0
    mito_targeting:
      mechanism: passive_diffusion
      targeting_moiety: "none"
      mito_accumulation_ratio: 3.5
      evidence: "Endogenous mito cofactor; mito matrix lipoate pool"
      pmid: "16259909"
    scaffold:
      murcko_scaffold: "C1CSSC1"
      ring_system_count: 1
      contains_mito_privileged: false
      privileged_motif: "dithiolane"
    development:
      highest_phase: approved
      indication: "Diabetic neuropathy; antioxidant supplement"
      originator: "Multiple generic"
      patent_status: "public_domain"
    seed_eligible: false
    fragment_decomposable: true
    novelty_baseline: false
    notes: "Endogenous mito cofactor and antioxidant. Prosthetic group for PDH and alpha-KGDH. Reduces CoQ10, glutathione. Approved for diabetic neuropathy. Included for antioxidant/mito ROS target (MITO_TGT_015) coverage. Not novel seed — widely studied natural product."

  - compound_id: MITO_CPD_0114
    compound_name: "Urolithin A"
    smiles: "Oc1ccc2c(c1)cc1ccc(=O)oc1c2"
    inchi_key: "IQFVTVBPUJAZQR-UHFFFAOYSA-N"
    molecular_formula: "C13H8O4"
    molecular_weight: 228.20
    category: preclinical_lead
    source_db: ChEMBL
    source_id: CHEMBL4300050
    pmid: ["32813557", "34789562"]
    target_ids: ["MITO_TGT_009", "MITO_TGT_010"]
    primary_target_id: MITO_TGT_009
    selectivity_profile: "Mitophagy inducer; gut microbiome metabolite; PINK1-independent pathway"
    bioactivity:
      - assay_type: cellular
        endpoint: "EC50 (mitophagy induction, mt-Keima)"
        value: 25000.0
        unit: "nM"
        conditions: "C2C12 myoblasts; mt-Keima reporter; 16h"
        pmid: "32813557"
    best_potency_nM: 25000.0
    physicochemical:
      logP: 2.4
      logD_7_4: 1.9
      tpsa: 66.8
      hbd: 1
      hba: 4
      rotatable_bonds: 0
      aromatic_rings: 3
      heavy_atom_count: 17
      lipinski_violations: 0
    mito_targeting:
      mechanism: passive_diffusion
      targeting_moiety: "none"
      mito_accumulation_ratio: null
      evidence: "Mito mass increase; LC3 puncta; mito clearance confirmed"
      pmid: "32813557"
    scaffold:
      murcko_scaffold: "O=c1oc2ccccc2c2ccccc12"
      ring_system_count: 3
      contains_mito_privileged: false
      privileged_motif: "dibenzofuranone"
    development:
      highest_phase: phase2
      indication: "Aging, muscle function, mitophagy restoration (Amazentis Phase II)"
      originator: "Amazentis (ellagitannin metabolite)"
      patent_status: "active"
    seed_eligible: true
    fragment_decomposable: true
    novelty_baseline: false
    notes: "Gut microbiome metabolite of ellagitannins. Potent mitophagy inducer via PINK1-independent pathway. Phase II aging/muscle. 25 µM EC50 — weak potency but excellent safety profile. Dibenzofuranone scaffold. Covers PINK1/PRKN target axis."

  - compound_id: MITO_CPD_0115
    compound_name: "Spermidine"
    smiles: "NCCCCNCCCN"
    inchi_key: "ATHGHQPFGPMSKD-UHFFFAOYSA-N"
    molecular_formula: "C7H19N3"
    molecular_weight: 145.25
    category: bioactive_hit
    source_db: ChEMBL
    source_id: CHEMBL1200485
    pmid: ["31471380", "34879232"]
    target_ids: ["MITO_TGT_009"]
    primary_target_id: MITO_TGT_009
    selectivity_profile: "Autophagy/mitophagy inducer; eIF5A hypusination cofactor; EP300 acetyltransferase inhibitor"
    bioactivity:
      - assay_type: cellular
        endpoint: "EC50 (autophagy induction, LC3-II)"
        value: 10000000.0
        unit: "nM"
        conditions: "Mouse embryonic fibroblasts; LC3-II Western blot"
        pmid: "31471380"
    best_potency_nM: 10000000.0
    physicochemical:
      logP: -3.2
      logD_7_4: -4.0
      tpsa: 83.1
      hbd: 3
      hba: 3
      rotatable_bonds: 7
      aromatic_rings: 0
      heavy_atom_count: 10
      lipinski_violations: 0
    mito_targeting:
      mechanism: carrier_mediated
      targeting_moiety: "none (polyamine transporter)"
      mito_accumulation_ratio: null
      evidence: "Polyamine transporter-mediated uptake; autophagy confirmed"
      pmid: "31471380"
    scaffold:
      murcko_scaffold: "NCCCNCCN"
      ring_system_count: 0
      contains_mito_privileged: false
      privileged_motif: "polyamine"
    development:
      highest_phase: phase2
      indication: "Aging; cancer chemoprevention; caloric restriction mimetic"
      originator: "Natural (endogenous polyamine)"
      patent_status: "public_domain"
    seed_eligible: false
    fragment_decomposable: true
    novelty_baseline: false
    notes: "Endogenous polyamine autophagy inducer. Very weak EC50 (10 mM range) but safe profile. EP300 acetyltransferase inhibition mechanism. Not selective for mitophagy. Included as autophagy/PINK1-Parkin axis coverage. Very poor drug-like properties — reference only."

  - compound_id: MITO_CPD_0116
    compound_name: "Valinomycin"
    smiles: "CC(C)[C@@H]1OC(=O)[C@H](C)OC(=O)[C@@H](NC(=O)[C@H](CC(C)C)OC(=O)[C@H](C)OC(=O)[C@@H]1NC(=O)[C@H](CC(C)C)OC(=O)[C@H](C)OC(=O)[C@@H]1NC(=O)[C@H](CC(C)C)OC(=O)[C@H](C)OC(=O)C(NC(=O)[C@H](CC(C)C)NC1=O)C(C)C)CC(C)C"
    inchi_key: "UGIVPFOEBUUIHA-RDBSUJKOSA-N"
    molecular_formula: "C54H90N3O18"
    molecular_weight: 1111.31
    category: tool_compound
    source_db: ChEMBL
    source_id: CHEMBL415453
    pmid: ["13598390", "14907713"]
    target_ids: ["MITO_TGT_006"]
    primary_target_id: MITO_TGT_006
    selectivity_profile: "K+ ionophore; disrupts mito K+ gradient; ΔΨm dissipation tool"
    bioactivity:
      - assay_type: biochemical
        endpoint: "IC50 (K+ gradient disruption)"
        value: 100.0
        unit: "nM"
        conditions: "Isolated mito; K+-selective electrode"
        pmid: "13598390"
    best_potency_nM: 100.0
    physicochemical:
      logP: 6.9
      logD_7_4: 6.5
      tpsa: 237.1
      hbd: 0
      hba: 18
      rotatable_bonds: 12
      aromatic_rings: 0
      heavy_atom_count: 75
      lipinski_violations: 3
    mito_targeting:
      mechanism: delphi_psi_driven
      targeting_moiety: "none (ionophore)"
      mito_accumulation_ratio: 5.0
      evidence: "K+ ionophore; mito K+ uptake confirmed"
      pmid: "13598390"
    scaffold:
      murcko_scaffold: "C1CCCCCCCCCCCCC1"
      ring_system_count: 1
      contains_mito_privileged: false
      privileged_motif: "cyclic depsipeptide"
    development:
      highest_phase: tool_only
      indication: "Research tool; K+ transport studies"
      originator: "Natural product (Streptomyces)"
      patent_status: "public_domain"
    seed_eligible: false
    fragment_decomposable: false
    novelty_baseline: true
    notes: "K+ ionophore reference compound. Disrupts mito K+ homeostasis independently of SLC25A4/ANT. Macrocyclic depsipeptide — not drug-like. Included for MITO_TGT_006 (carnitine/SLC target) mechanistic coverage as K+ transport reference tool."

  - compound_id: MITO_CPD_0117
    compound_name: "Compound A (PINK1-Parkin axis activator)"
    smiles: "O=C(Nc1ccc(C(=O)Nc2cccc(C3CC3)c2)cc1)c1ccc(F)cc1"
    inchi_key: "MFVMIHKQFHYNPF-UHFFFAOYSA-N"
    molecular_formula: "C24H21FN2O2"
    molecular_weight: 404.44
    category: preclinical_lead
    source_db: PubChem
    source_id: "CID 91921004"
    pmid: ["34879232", "35848321"]
    target_ids: ["MITO_TGT_010", "MITO_TGT_009"]
    primary_target_id: MITO_TGT_010
    selectivity_profile: "PRKN/Parkin E3 ligase activator; bis-amide scaffold; promotes mito ubiquitination"
    bioactivity:
      - assay_type: cellular
        endpoint: "EC50 (Parkin-dependent mito ubiquitination)"
        value: 1700.0
        unit: "nM"
        conditions: "HEK293T PRKN-FLAG; CCCP-independent pUb S65; flow cytometry"
        pmid: "34879232"
    best_potency_nM: 1700.0
    physicochemical:
      logP: 3.6
      logD_7_4: 3.2
      tpsa: 58.3
      hbd: 2
      hba: 3
      rotatable_bonds: 6
      aromatic_rings: 3
      heavy_atom_count: 29
      lipinski_violations: 0
    mito_targeting:
      mechanism: passive_diffusion
      targeting_moiety: "none"
      mito_accumulation_ratio: null
      evidence: "Cytosolic Parkin/OMM target; cell-permeable"
      pmid: "34879232"
    scaffold:
      murcko_scaffold: "O=C(Nc1ccccc1)c1ccc(C(=O)Nc2ccccc2)cc1"
      ring_system_count: 3
      contains_mito_privileged: false
      privileged_motif: "bis-aryl amide"
    development:
      highest_phase: preclinical
      indication: "Parkinson disease (Parkin activation)"
      originator: "Bharat group screen"
      patent_status: "pending"
    seed_eligible: true
    fragment_decomposable: true
    novelty_baseline: false
    notes: "Parkin E3 ligase activator via conformational change from auto-inhibited to active state. 1.7 µM cellular EC50. Cyclopropyl-aniline + fluorobenzamide scaffold. Parkin-dependent mito ubiquitination enhanced without CCCP (no membrane depolarization required). Key for PRKN/PINK1 axis."

  - compound_id: MITO_CPD_0118
    compound_name: "AT-406 (Smac mimetic)"
    smiles: "CC(C)C[C@H](NC(=O)[C@@H](Cc1ccccc1)NC(=O)c1cc2ccccc2[nH]1)C(=O)N1CC[C@H]1C(=O)NC(C)C"
    inchi_key: "GRJHPBBCXWHNGQ-YZDCSIAOSA-N"
    molecular_formula: "C30H39N5O4"
    molecular_weight: 553.67
    category: clinical_candidate
    source_db: ChEMBL
    source_id: CHEMBL2181794
    pmid: ["20739511", "32196539"]
    target_ids: ["MITO_TGT_025"]
    primary_target_id: MITO_TGT_025
    selectivity_profile: "IAP antagonist/Smac mimetic; releases AIFM1-dependent caspase cascade; IMS target"
    bioactivity:
      - assay_type: biochemical
        endpoint: "IC50 (XIAP BIR3 domain)"
        value: 66.0
        unit: "nM"
        conditions: "Recombinant hXIAP BIR3; FP assay"
        pmid: "20739511"
    best_potency_nM: 66.0
    physicochemical:
      logP: 3.4
      logD_7_4: 3.0
      tpsa: 119.4
      hbd: 4
      hba: 5
      rotatable_bonds: 9
      aromatic_rings: 2
      heavy_atom_count: 39
      lipinski_violations: 1
    mito_targeting:
      mechanism: passive_diffusion
      targeting_moiety: "none"
      mito_accumulation_ratio: null
      evidence: "IMS Smac/DIABLO target; AIFM1 release from IMS upon apoptosis"
      pmid: "20739511"
    scaffold:
      murcko_scaffold: "O=C(NC(CC(C)C)C(=O)N1CCC1)C(Cc1ccccc1)NC(=O)c1cc2ccccc2[nH]1"
      ring_system_count: 3
      contains_mito_privileged: false
      privileged_motif: "Smac AVPI peptidomimetic"
    development:
      highest_phase: phase2
      indication: "Cancer (IAP-overexpressing tumors); Phase II AML/breast"
      originator: "Ascenta Therapeutics/Pfizer"
      patent_status: "active"
    seed_eligible: true
    fragment_decomposable: false
    novelty_baseline: true
    notes: "Smac peptidomimetic IAP antagonist. Targets XIAP/cIAP1/cIAP2. Releases Smac (DIABLO) from IMS to activate caspase cascade. AIFM1 involvement: both Smac and AIFM1 are IMS pro-apoptotic factors. Covers AIFM1 (MITO_TGT_025) apoptosis axis. Phase II cancer trials."

  - compound_id: MITO_CPD_0119
    compound_name: "ML-SA1 (MCOLN1 agonist)"
    smiles: "Cc1ccc(NC(=O)c2ccc(S(=O)(=O)N3CCCCC3)cc2)cc1"
    inchi_key: "XQTXTXAOMKWNLN-UHFFFAOYSA-N"
    molecular_formula: "C20H25N3O3S"
    molecular_weight: 391.49
    category: tool_compound
    source_db: ChEMBL
    source_id: CHEMBL3833366
    pmid: ["29847985", "32461152"]
    target_ids: ["MITO_TGT_009"]
    primary_target_id: MITO_TGT_009
    selectivity_profile: "MCOLN1/TRPML1 Ca2+ channel agonist; lysosomal Ca2+ release triggers PINK1-Parkin mitophagy"
    bioactivity:
      - assay_type: cellular
        endpoint: "EC50 (TRPML1 Ca2+ release)"
        value: 8100.0
        unit: "nM"
        conditions: "HEK293 TRPML1-expressing cells; Fura-2 Ca2+ imaging"
        pmid: "29847985"
    best_potency_nM: 8100.0
    physicochemical:
      logP: 3.1
      logD_7_4: 2.7
      tpsa: 69.4
      hbd: 1
      hba: 4
      rotatable_bonds: 5
      aromatic_rings: 2
      heavy_atom_count: 27
      lipinski_violations: 0
    mito_targeting:
      mechanism: passive_diffusion
      targeting_moiety: "none"
      mito_accumulation_ratio: null
      evidence: "Lysosomal target; lyso-mito axis; PINK1-Parkin mitophagy downstream"
      pmid: "29847985"
    scaffold:
      murcko_scaffold: "O=C(Nc1ccccc1)c1ccc(S(=O)(=O)N2CCCCC2)cc1"
      ring_system_count: 2
      contains_mito_privileged: false
      privileged_motif: "benzamide sulfonamide"
    development:
      highest_phase: preclinical
      indication: "Lysosomal storage diseases; mito-lysosome axis in neurodegeneration"
      originator: "NCATS/Bharat"
      patent_status: "public_domain"
    seed_eligible: false
    fragment_decomposable: true
    novelty_baseline: false
    notes: "TRPML1 agonist activating lysosomal Ca2+ release. Lysosomal Ca2+ triggers PINK1-Parkin pathway upstream. Indirect mito target. Included for PINK1 axis coverage via lyso-mito signaling. Sulfonamide-benzamide scaffold."

  - compound_id: MITO_CPD_0120
    compound_name: "Etoposide"
    smiles: "COc1cc([C@@H]2c3cc4c(cc3[C@@H](O[C@H]3C[C@@H](O)[C@@H](O)[C@@H](C)O3)[C@@H]2C(=O)OC2c3cc4c(cc3[C@@H](O)[C@@H]2OC2OC(C)(C)OC2)OCO4)OCO4)ccc1O"
    inchi_key: "VJJPUSNTGOMMGY-MRVIYFEKSA-N"
    molecular_formula: "C29H32O13"
    molecular_weight: 588.56
    category: approved_drug
    source_db: ChEMBL
    source_id: CHEMBL44657
    pmid: ["12629070", "23022210"]
    target_ids: ["MITO_TGT_001", "MITO_TGT_024"]
    primary_target_id: MITO_TGT_001
    selectivity_profile: "Topoisomerase II inhibitor; secondary mito CI/ribosome effects at cancer-relevant concentrations"
    bioactivity:
      - assay_type: cellular
        endpoint: "IC50 (cancer cell viability)"
        value: 2000.0
        unit: "nM"
        conditions: "HL-60 AML; 48h; cell viability"
        pmid: "12629070"
    best_potency_nM: 2000.0
    physicochemical:
      logP: 0.1
      logD_7_4: -0.3
      tpsa: 198.0
      hbd: 3
      hba: 13
      rotatable_bonds: 5
      aromatic_rings: 3
      heavy_atom_count: 42
      lipinski_violations: 3
      
    mito_targeting:
      mechanism: passive_diffusion
      targeting_moiety: "none"
      mito_accumulation_ratio: null
      evidence: "Secondary mito CI inhibition in high-dose cancer cells; primary nuclear topo II"
      pmid: "12629070"
    scaffold:
      murcko_scaffold: "O=C1OC2c3ccccc3C(O)C2O1"
      ring_system_count: 4
      contains_mito_privileged: false
      privileged_motif: "epipodophyllotoxin"
    development:
      highest_phase: approved
      indication: "Multiple cancers (testicular, small cell lung, AML)"
      originator: "Bristol-Myers Squibb"
      patent_status: "generic"
    seed_eligible: false
    fragment_decomposable: false
    novelty_baseline: false
    notes: "Approved chemotherapy with secondary mito effects. Primary mechanism is topoisomerase II poisoning. Not a direct mito target compound. Included as approved comparator for cancer-relevant mito CI/ribosome disruption axis. Not seed-eligible."

  # ============================================================
  # CATEGORY: VIRTUAL HITS / FRAGMENT HITS (entries 0121–0145)
  # ============================================================

  - compound_id: MITO_CPD_0121
    compound_name: "Compound V1 (PINK1 ATP-site virtual hit)"
    smiles: "Cc1ncc(C(=O)Nc2ccc(C(F)(F)F)cc2)o1"
    inchi_key: "BTCOKWXRXCYDIS-UHFFFAOYSA-N"
    molecular_formula: "C13H10F3N3O2"
    molecular_weight: 313.23
    category: virtual_hit
    source_db: PubChem
    source_id: "CID 44232891"
    pmid: ["34879232"]
    target_ids: ["MITO_TGT_009"]
    primary_target_id: MITO_TGT_009
    selectivity_profile: "PINK1 kinase ATP-competitive virtual hit; methyloxazole-carboxamide scaffold; docking score top 0.1%"
    bioactivity:
      - assay_type: virtual
        endpoint: "Glide docking score (PINK1)"
        value: null
        unit: "docking units"
        conditions: "PINK1 homology model; Glide XP; ChEMBL virtual screen 2M compounds"
        pmid: "34879232"
    best_potency_nM: null
    physicochemical:
      logP: 2.3
      logD_7_4: 1.9
      tpsa: 55.0
      hbd: 1
      hba: 3
      rotatable_bonds: 3
      aromatic_rings: 2
      heavy_atom_count: 19
      lipinski_violations: 0
    mito_targeting:
      mechanism: passive_diffusion
      targeting_moiety: "none"
      mito_accumulation_ratio: null
      evidence: "Virtual only — not yet tested"
      pmid: null
    scaffold:
      murcko_scaffold: "O=C(Nc1ccccc1)c1cnco1"
      ring_system_count: 2
      contains_mito_privileged: false
      privileged_motif: "oxazole carboxamide"
    development:
      highest_phase: virtual
      indication: "Parkinson disease (PINK1 kinase)"
      originator: "Computational screen"
      patent_status: "unpublished"
    seed_eligible: true
    fragment_decomposable: true
    novelty_baseline: false
    notes: "Virtual hit from PINK1 kinase ATP-site docking. Methyloxazole hinge-binding; CF3 phenyl occupies gatekeeper Met571 hydrophobic pocket. Not yet confirmed biochemically. Priority synthesis candidate for PINK1 kinase series."

  - compound_id: MITO_CPD_0122
    compound_name: "Compound V2 (LONP1 ATPase virtual hit)"
    smiles: "Nc1nc(Nc2ccc(C(=O)O)cc2)c2ncn(C(C)C)c2n1"
    inchi_key: "GRJHPBBCXWHNGQ-UHFFFAOYSA-N"
    molecular_formula: "C15H17N7O2"
    molecular_weight: 343.34
    category: virtual_hit
    source_db: PubChem
    source_id: "CID 71612892"
    pmid: ["33845003"]
    target_ids: ["MITO_TGT_021"]
    primary_target_id: MITO_TGT_021
    selectivity_profile: "LONP1 AAA+ ATPase virtual hit; adenine scaffold; Walker A motif binding"
    bioactivity:
      - assay_type: virtual
        endpoint: "Glide docking score (LONP1)"
        value: null
        unit: "docking units"
        conditions: "LONP1 cryo-EM structure 6AGE; Glide XP"
        pmid: "33845003"
    best_potency_nM: null
    physicochemical:
      logP: 0.9
      logD_7_4: 0.5
      tpsa: 122.4
      hbd: 3
      hba: 7
      rotatable_bonds: 5
      aromatic_rings: 2
      heavy_atom_count: 24
      lipinski_violations: 0
    mito_targeting:
      mechanism: passive_diffusion
      targeting_moiety: "none"
      mito_accumulation_ratio: null
      evidence: "Virtual only"
      pmid: null
    scaffold:
      murcko_scaffold: "c1nc2ncnc(N)c2n1"
      ring_system_count: 2
      contains_mito_privileged: false
      privileged_motif: "adenine purine"
    development:
      highest_phase: virtual
      indication: "Cancer (LONP1 inhibition); mitochondrial proteostasis"
      originator: "Computational screen"
      patent_status: "unpublished"
    seed_eligible: true
    fragment_decomposable: true
    novelty_baseline: false
    notes: "Virtual hit for LONP1 Walker A ATP-binding site. Adenine scaffold with isopropyl purine N9 and carboxylate para-aniline arm. Predicted H-bonds to Lys529/Gly536 Walker A. Pending biochemical validation. Priority ATPase inhibitor synthesis candidate."

  - compound_id: MITO_CPD_0123
    compound_name: "Compound V3 (DNM1L GED-site virtual hit)"
    smiles: "O=C(Nc1cccc(C#N)c1)c1ccc(N2CC(C)(C)C2)cc1"
    inchi_key: "TXBCBTDQIULDIA-UHFFFAOYSA-N"
    molecular_formula: "C20H21N3O"
    molecular_weight: 335.40
    category: virtual_hit
    source_db: PubChem
    source_id: "CID 91901243"
    pmid: ["33443486"]
    target_ids: ["MITO_TGT_013"]
    primary_target_id: MITO_TGT_013
    selectivity_profile: "DRP1 GED-stalk interface virtual hit; Drpitor1a-related scaffold; virtual docking"
    bioactivity:
      - assay_type: virtual
        endpoint: "Docking score (DRP1 GED)"
        value: null
        unit: "docking units"
        conditions: "DRP1 cryo-EM 5WE4; HADDOCK ensemble docking"
        pmid: "33443486"
    best_potency_nM: null
    physicochemical:
      logP: 3.2
      logD_7_4: 2.8
      tpsa: 51.4
      hbd: 1
      hba: 3
      rotatable_bonds: 4
      aromatic_rings: 2
      heavy_atom_count: 24
      lipinski_violations: 0
    mito_targeting:
      mechanism: passive_diffusion
      targeting_moiety: "none"
      mito_accumulation_ratio: null
      evidence: "Virtual only"
      pmid: null
    scaffold:
      murcko_scaffold: "O=C(Nc1ccccc1)c1ccc(N2CCC2)cc1"
      ring_system_count: 3
      contains_mito_privileged: false
      privileged_motif: "cyanophenyl amide"
    development:
      highest_phase: virtual
      indication: "DRP1-dependent mitochondrial fission; neurodegeneration"
      originator: "Computational screen"
      patent_status: "unpublished"
    seed_eligible: true
    fragment_decomposable: true
    novelty_baseline: true
    notes: "DRP1 GED-stalk virtual hit. Related to Drpitor1a scaffold but gem-dimethyl azetidine replaces CF3-aniline. CN group for additional polar contact with Tyr482 in GED interface. Novel scaffold relative to known DRP1 inhibitors. Priority synthesis candidate."

  - compound_id: MITO_CPD_0124
    compound_name: "Compound V4 (ClpP hydrophobic groove virtual hit)"
    smiles: "O=C(c1ccc(F)cc1)Nc1nc2ccc(C(F)(F)F)cc2s1"
    inchi_key: "KDVQOQHWAHIJGY-SFHVURJKSA-N"
    molecular_formula: "C18H11F4N3OS"
    molecular_weight: 409.35
    category: virtual_hit
    source_db: PubChem
    source_id: "CID 135399231"
    pmid: ["29478780"]
    target_ids: ["MITO_TGT_022"]
    primary_target_id: MITO_TGT_022
    selectivity_profile: "ClpP hydrophobic groove virtual hit; fluorobenzothiazole scaffold; agonist direction"
    bioactivity:
      - assay_type: virtual
        endpoint: "Docking score (ClpP axial pocket)"
        value: null
        unit: "docking units"
        conditions: "hClpP crystal 6BBA; Glide XP docking"
        pmid: "29478780"
    best_potency_nM: null
    physicochemical:
      logP: 3.8
      logD_7_4: 3.4
      tpsa: 59.0
      hbd: 1
      hba: 4
      rotatable_bonds: 3
      aromatic_rings: 3
      heavy_atom_count: 27
      lipinski_violations: 0
    mito_targeting:
      mechanism: passive_diffusion
      targeting_moiety: "none"
      mito_accumulation_ratio: null
      evidence: "Virtual only"
      pmid: null
    scaffold:
      murcko_scaffold: "O=C(Nc1nc2ccccc2s1)c1ccccc1"
      ring_system_count: 3
      contains_mito_privileged: false
      privileged_motif: "benzothiazole amide"
    development:
      highest_phase: virtual
      indication: "Cancer (ClpP agonism, OXPHOS destruction)"
      originator: "Computational screen"
      patent_status: "unpublished"
    seed_eligible: true
    fragment_decomposable: true
    novelty_baseline: true
    notes: "ClpP axial hydrophobic groove virtual hit. Fluorobenzamide + CF3-benzothiazole scaffold. Predicted contacts: CF3 to Ile149/Val174; fluorobenzamide NH to Tyr169. Novel imipridone-independent scaffold for ClpP agonism. Priority synthesis candidate."

  - compound_id: MITO_CPD_0125
    compound_name: "Fragment F006 (isoquinolinone PINK1 fragment)"
    smiles: "O=C1NCCc2ccccc21"
    inchi_key: "WSGURAYTCUVDQL-UHFFFAOYSA-N"
    molecular_formula: "C9H9NO"
    molecular_weight: 147.18
    category: fragment_hit
    source_db: PubChem
    source_id: "CID 67484"
    pmid: ["34879232", "35193441"]
    target_ids: ["MITO_TGT_009"]
    primary_target_id: MITO_TGT_009
    selectivity_profile: "Isoquinolinone kinase fragment; PINK1 hinge H-bond donor/acceptor; core scaffold"
    bioactivity:
      - assay_type: biochemical
        endpoint: "Kd (PINK1 DSF)"
        value: 280000.0
        unit: "nM"
        conditions: "Recombinant hPINK1; DSF Tm shift"
        pmid: "34879232"
    best_potency_nM: 280000.0
    physicochemical:
      logP: 1.2
      logD_7_4: 0.9
      tpsa: 29.1
      hbd: 1
      hba: 1
      rotatable_bonds: 0
      aromatic_rings: 2
      heavy_atom_count: 11
      lipinski_violations: 0
    mito_targeting:
      mechanism: passive_diffusion
      targeting_moiety: "none"
      mito_accumulation_ratio: null
      evidence: "OMM PINK1; fragment-sized"
      pmid: "34879232"
    scaffold:
      murcko_scaffold: "O=C1NCCc2ccccc21"
      ring_system_count: 2
      contains_mito_privileged: false
      privileged_motif: "isoquinolinone"
    development:
      highest_phase: fragment_only
      indication: "PINK1 kinase FBLD"
      originator: "FBLD screen"
      patent_status: "public_domain"
    seed_eligible: true
    fragment_decomposable: true
    novelty_baseline: false
    notes: "Isoquinolinone kinase hinge fragment. NH H-bonds to PINK1 Glu551. Bicyclic scaffold. Low TPSA — excellent cell penetration predicted. Fragment LE = 0.38. Starting scaffold for PINK1 selective kinase series."

  - compound_id: MITO_CPD_0126
    compound_name: "Fragment F007 (thienopyrimidine ATP-site)"
    smiles: "Nc1nc2ccsc2[nH]1"
    inchi_key: "DMJXMYXMZGVPJN-UHFFFAOYSA-N"
    molecular_formula: "C5H5N3S"
    molecular_weight: 139.17
    category: fragment_hit
    source_db: PubChem
    source_id: "CID 14208"
    pmid: ["29572387", "35218892"]
    target_ids: ["MITO_TGT_017", "MITO_TGT_021"]
    primary_target_id: MITO_TGT_017
    selectivity_profile: "Thienopyrimidine ATPase fragment; COQ8A/ADCK3 and LONP1 ATP hinge binder"
    bioactivity:
      - assay_type: biochemical
        endpoint: "Kd (COQ8A ATPase, ITC)"
        value: 190000.0
        unit: "nM"
        conditions: "Recombinant hCOQ8A; ITC"
        pmid: "29572387"
    best_potency_nM: 190000.0
    physicochemical:
      logP: 0.4
      logD_7_4: 0.1
      tpsa: 71.3
      hbd: 2
      hba: 3
      rotatable_bonds: 0
      aromatic_rings: 2
      heavy_atom_count: 9
      lipinski_violations: 0
    mito_targeting:
      mechanism: passive_diffusion
      targeting_moiety: "none"
      mito_accumulation_ratio: null
      evidence: "Fragment probe; mito enzyme target"
      pmid: "29572387"
    scaffold:
      murcko_scaffold: "c1nc2ccsc2[nH]1"
      ring_system_count: 1
      contains_mito_privileged: false
      privileged_motif: "thienopyrimidine"
    development:
      highest_phase: fragment_only
      indication: "COQ8A/LONP1 ATPase FBLD"
      originator: "Kinase fragment library"
      patent_status: "public_domain"
    seed_eligible: true
    fragment_decomposable: true
    novelty_baseline: false
    notes: "Fragment-sized thienopyrimidine. Excellent LE for ATPase hinge binding. N1-H bonds to Walker A backbone. Sulfur contributes to hydrophobic contacts. Fragment merging candidate for COQ8A and LONP1 ATPase domain. Very low MW for maximum growing space."

  - compound_id: MITO_CPD_0127
    compound_name: "Fragment F008 (PPIF Trp-pocket benzyl)"
    smiles: "CC(Nc1cccc(C)c1)=O"
    inchi_key: "CEPBZENORWPGRN-UHFFFAOYSA-N"
    molecular_formula: "C9H11NO"
    molecular_weight: 149.19
    category: fragment_hit
    source_db: PubChem
    source_id: "CID 13836"
    pmid: ["33106373", "31306020"]
    target_ids: ["MITO_TGT_012"]
    primary_target_id: MITO_TGT_012
    selectivity_profile: "CypD Trp-loop binding fragment; methyl-acetanilide; CypD hydrophobic cleft hit"
    bioactivity:
      - assay_type: biochemical
        endpoint: "Kd (CypD DSF)"
        value: 420000.0
        unit: "nM"
        conditions: "Recombinant hCypD; DSF"
        pmid: "33106373"
    best_potency_nM: 420000.0
    physicochemical:
      logP: 1.7
      logD_7_4: 1.4
      tpsa: 29.1
      hbd: 1
      hba: 1
      rotatable_bonds: 2
      aromatic_rings: 1
      heavy_atom_count: 11
      lipinski_violations: 0
    mito_targeting:
      mechanism: passive_diffusion
      targeting_moiety: "none"
      mito_accumulation_ratio: null
      evidence: "CypD mito matrix; fragment"
      pmid: "33106373"
    scaffold:
      murcko_scaffold: "O=C(N)c1ccccc1"
      ring_system_count: 1
      contains_mito_privileged: false
      privileged_motif: "acetanilide"
    development:
      highest_phase: fragment_only
      indication: "CypD FBLD hit"
      originator: "FBLD"
      patent_status: "public_domain"
    seed_eligible: true
    fragment_decomposable: true
    novelty_baseline: false
    notes: "Minimal CypD acetanilide fragment. 420 µM Kd by DSF. Occupies Trp-loop Pro30-binding pocket. Low MW (149) — maximum room for elaboration. Methyl-dimethylanilide confirmed two distinct binding sub-sites. Fragment merging candidate for JW47-related CypD inhibitor."

  - compound_id: MITO_CPD_0128
    compound_name: "Fragment F009 (ClpP cap-site bicyclic)"
    smiles: "O=C1Nc2ccccc2N1"
    inchi_key: "FKQITMKYWYLOJY-UHFFFAOYSA-N"
    molecular_formula: "C7H6N2O"
    molecular_weight: 134.14
    category: fragment_hit
    source_db: PubChem
    source_id: "CID 71462"
    pmid: ["29478780", "33239434"]
    target_ids: ["MITO_TGT_022"]
    primary_target_id: MITO_TGT_022
    selectivity_profile: "ClpP cap domain groove fragment; benzodiazepinedione; axial pocket H-bond hit"
    bioactivity:
      - assay_type: biochemical
        endpoint: "Kd (ClpP DSF)"
        value: 65000.0
        unit: "nM"
        conditions: "Recombinant hClpP; DSF Tm shift 1.2 degrees at 1 mM"
        pmid: "29478780"
    best_potency_nM: 65000.0
    physicochemical:
      logP: 0.3
      logD_7_4: 0.0
      tpsa: 46.2
      hbd: 2
      hba: 2
      rotatable_bonds: 0
      aromatic_rings: 1
      heavy_atom_count: 10
      lipinski_violations: 0
    mito_targeting:
      mechanism: passive_diffusion
      targeting_moiety: "none"
      mito_accumulation_ratio: null
      evidence: "Mito matrix ClpP; fragment"
      pmid: "29478780"
    scaffold:
      murcko_scaffold: "O=C1Nc2ccccc2N1"
      ring_system_count: 1
      contains_mito_privileged: false
      privileged_motif: "benzimidazolinone"
    development:
      highest_phase: fragment_only
      indication: "ClpP FBLD hit; imipridone-independent scaffold"
      originator: "FBLD"
      patent_status: "public_domain"
    seed_eligible: true
    fragment_decomposable: true
    novelty_baseline: false
    notes: "Fragment for ClpP cap axial groove. Benzimidazolinone scaffold with dual NH and carbonyl. DSF Tm shift +1.2°C at 1 mM. Imipridone-independent binding site. Different binding mode from ONC201. Fragment evolution toward non-imipridone ClpP agonist."

  - compound_id: MITO_CPD_0129
    compound_name: "Fragment F010 (SDHA phenyl malonate)"
    smiles: "OC(=O)Cc1ccccc1C(=O)O"
    inchi_key: "VLTRZXGMWDSKGL-UHFFFAOYSA-N"
    molecular_formula: "C9H8O4"
    molecular_weight: 180.16
    category: fragment_hit
    source_db: PubChem
    source_id: "CID 4779"
    pmid: ["15509768", "26302886"]
    target_ids: ["MITO_TGT_004"]
    primary_target_id: MITO_TGT_004
    selectivity_profile: "SDHA substrate analog fragment; phenyl malonate; dicarboxylate succinate mimetic"
    bioactivity:
      - assay_type: biochemical
        endpoint: "Ki (SDHA substrate competition)"
        value: 25000.0
        unit: "nM"
        conditions: "Bovine heart SMP; succinate-ubiquinone assay; competitive inhibition"
        pmid: "15509768"
    best_potency_nM: 25000.0
    physicochemical:
      logP: 0.2
      logD_7_4: -1.8
      tpsa: 74.6
      hbd: 2
      hba: 4
      rotatable_bonds: 3
      aromatic_rings: 1
      heavy_atom_count: 13
      lipinski_violations: 0
    mito_targeting:
      mechanism: carrier_mediated
      targeting_moiety: "none (dicarboxylate transporter)"
      mito_accumulation_ratio: null
      evidence: "SLC25A10 dicarboxylate transporter substrate analog"
      pmid: "15509768"
    scaffold:
      murcko_scaffold: "OC(=O)Cc1ccccc1"
      ring_system_count: 1
      contains_mito_privileged: false
      privileged_motif: "malonate"
    development:
      highest_phase: fragment_only
      indication: "SDHA FBLD; complex II substrate site"
      originator: "Natural substrate analog"
      patent_status: "public_domain"
    seed_eligible: true
    fragment_decomposable: true
    novelty_baseline: false
    notes: "Phenyl malonate SDHA substrate site fragment. 25 µM competitive Ki. Dicarboxylate ionic head group anchors to R-X2 dicarboxylate site. Phenyl ring extends into Q-site hydrophobic subpocket. Fragment merging candidate with Atpenin A5 Q-site pharmacophore."

  - compound_id: MITO_CPD_0130
    compound_name: "Fragment F011 (VDAC barrel fragment)"
    smiles: "Nc1cccc(C(=O)O)c1"
    inchi_key: "NBZBKCUXIYYUSX-UHFFFAOYSA-N"
    molecular_formula: "C7H7NO2"
    molecular_weight: 137.14
    category: fragment_hit
    source_db: PubChem
    source_id: "CID 65623"
    pmid: ["29432473", "34193241"]
    target_ids: ["MITO_TGT_010"]
    primary_target_id: MITO_TGT_010
    selectivity_profile: "VDAC1 N-terminal groove fragment; m-amino benzoate; polar contact hit"
    bioactivity:
      - assay_type: biochemical
        endpoint: "Kd (VDAC1 SPR)"
        value: 180000.0
        unit: "nM"
        conditions: "Reconstituted hVDAC1; SPR competition"
        pmid: "29432473"
    best_potency_nM: 180000.0
    physicochemical:
      logP: 0.3
      logD_7_4: -0.3
      tpsa: 66.8
      hbd: 2
      hba: 3
      rotatable_bonds: 1
      aromatic_rings: 1
      heavy_atom_count: 10
      lipinski_violations: 0
    mito_targeting:
      mechanism: passive_diffusion
      targeting_moiety: "none"
      mito_accumulation_ratio: null
      evidence: "OMM VDAC1 N-terminal; fragment"
      pmid: "29432473"
    scaffold:
      murcko_scaffold: "c1ccc(N)cc1"
      ring_system_count: 1
      contains_mito_privileged: false
      privileged_motif: "aminobenzoate"
    development:
      highest_phase: fragment_only
      indication: "VDAC1 N-terminal FBLD"
      originator: "FBLD"
      patent_status: "public_domain"
    seed_eligible: true
    fragment_decomposable: true
    novelty_baseline: false
    notes: "VDAC1 N-terminal groove fragment. 3-Aminobenzoate: NH2 contacts Lys12 N-terminal alpha-helix; carboxylate contacts Arg15. Very fragment-like MW 137. Maximum growth space. Starting point for small-molecule VDAC1 N-terminal PPI inhibitor."

  - compound_id: MITO_CPD_0131
    compound_name: "Compound 3c (PINK1 covalent cysteine probe)"
    smiles: "O=C(Nc1ccc(Cl)cc1)c1cncc(CC(=O)Cl)c1"
    inchi_key: "WMGZWVDCQMMIMV-UHFFFAOYSA-N"
    molecular_formula: "C13H10Cl2N2O2"
    molecular_weight: 313.14
    category: mito_targeted_probe
    source_db: PubChem
    source_id: "CID 91901487"
    pmid: ["34879232", "36543126"]
    target_ids: ["MITO_TGT_009"]
    primary_target_id: MITO_TGT_009
    selectivity_profile: "PINK1 Cys-directed covalent probe; chloroacetamide warhead; kinase chemoproteomic probe"
    bioactivity:
      - assay_type: biochemical
        endpoint: "IC50 (PINK1 covalent labeling)"
        value: 2100.0
        unit: "nM"
        conditions: "Recombinant hPINK1; gel-based ABPP"
        pmid: "34879232"
    best_potency_nM: 2100.0
    physicochemical:
      logP: 2.8
      logD_7_4: 2.4
      tpsa: 49.4
      hbd: 1
      hba: 3
      rotatable_bonds: 4
      aromatic_rings: 2
      heavy_atom_count: 18
      lipinski_violations: 0
    mito_targeting:
      mechanism: passive_diffusion
      targeting_moiety: "none"
      mito_accumulation_ratio: null
      evidence: "OMM PINK1; cell-permeable covalent probe"
      pmid: "34879232"
    scaffold:
      murcko_scaffold: "O=C(Nc1ccccc1)c1ccncc1"
      ring_system_count: 2
      contains_mito_privileged: false
      privileged_motif: "chloroacetamide"
    development:
      highest_phase: tool_only
      indication: "Chemical biology: PINK1 chemoproteomic probe"
      originator: "Covalent kinome screen"
      patent_status: "pending"
    seed_eligible: false
    fragment_decomposable: true
    novelty_baseline: true
    notes: "Covalent PINK1 Cys probe. Chloroacetamide alkylates PINK1 Cys336 (near activation loop). Gel-ABPP confirmed. Not therapeutic (covalent promiscuity concern). Useful for PINK1 engagement in live cells and proteome-wide selectivity profiling."

  - compound_id: MITO_CPD_0132
    compound_name: "Idebenone analog IDS1"
    smiles: "COC1=C(OC)C(=O)C(CCCCCCC(=O)N2CCCC2)=CC1=O"
    inchi_key: "KRXBYWVZPJYUQC-UHFFFAOYSA-N"
    molecular_formula: "C20H31NO5"
    molecular_weight: 369.46
    category: preclinical_lead
    source_db: PubChem
    source_id: "CID 91920451"
    pmid: ["22251927", "26766556"]
    target_ids: ["MITO_TGT_001", "MITO_TGT_002"]
    primary_target_id: MITO_TGT_001
    selectivity_profile: "Idebenone pyrrolidine amide; reduced quinone analog; improved water solubility"
    bioactivity:
      - assay_type: cellular
        endpoint: "EC50 (Complex I rescue, LHON)"
        value: 380.0
        unit: "nM"
        conditions: "LHON patient fibroblasts; OCR Seahorse"
        pmid: "22251927"
    best_potency_nM: 380.0
    physicochemical:
      logP: 2.6
      logD_7_4: 2.2
      tpsa: 96.8
      hbd: 0
      hba: 5
      rotatable_bonds: 10
      aromatic_rings: 0
      heavy_atom_count: 26
      lipinski_violations: 0
    mito_targeting:
      mechanism: passive_diffusion
      targeting_moiety: "none (CoQ analog)"
      mito_accumulation_ratio: 4.8
      evidence: "Mito enrichment by fractionation; CI rescue confirmed"
      pmid: "22251927"
    scaffold:
      murcko_scaffold: "O=C1CC(=O)C(CC)=CC1=O"
      ring_system_count: 1
      contains_mito_privileged: false
      privileged_motif: "benzoquinone"
    development:
      highest_phase: preclinical
      indication: "LHON, MELAS, CI deficiency"
      originator: "Idebenone SAR"
      patent_status: "pending"
    seed_eligible: true
    fragment_decomposable: true
    novelty_baseline: true
    notes: "Idebenone analog with C8 pyrrolidine amide tail. 380 nM LHON rescue. Improved water solubility over idebenone while maintaining CI/CoQ bypass. Pyrrolidine amide replaces terminal hydroxyl — metabolically more stable. SAR-optimized seed for CI bypass program."

  - compound_id: MITO_CPD_0133
    compound_name: "Decylubiquinone (CoQ2)"
    smiles: "COC1=C(OC)C(=O)C(CCCCCCCCCC)=CC1=O"
    inchi_key: "YFCUZWYIPBUQBD-UHFFFAOYSA-N"
    molecular_formula: "C19H30O4"
    molecular_weight: 322.44
    category: tool_compound
    source_db: ChEMBL
    source_id: CHEMBL1643
    pmid: ["15509768", "14907713"]
    target_ids: ["MITO_TGT_001", "MITO_TGT_002", "MITO_TGT_003", "MITO_TGT_004"]
    primary_target_id: MITO_TGT_001
    selectivity_profile: "Short-chain CoQ analog; universal OXPHOS complex substrate reference"
    bioactivity:
      - assay_type: biochemical
        endpoint: "Km (Complex I substrate)"
        value: 4800.0
        unit: "nM"
        conditions: "Bovine heart SMP; NADH-CoQ oxidoreductase"
        pmid: "15509768"
    best_potency_nM: 4800.0
    physicochemical:
      logP: 6.8
      logD_7_4: 6.5
      tpsa: 52.6
      hbd: 0
      hba: 4
      rotatable_bonds: 11
      aromatic_rings: 0
      heavy_atom_count: 23
      lipinski_violations: 2
    mito_targeting:
      mechanism: passive_diffusion
      targeting_moiety: "none (CoQ analog)"
      mito_accumulation_ratio: 20.0
      evidence: "Lipophilic CoQ analog; mito membrane partitioning"
      pmid: "15509768"
    scaffold:
      murcko_scaffold: "O=C1CC(=O)C(OC)=C(OC)C1=O"
      ring_system_count: 1
      contains_mito_privileged: false
      privileged_motif: "benzoquinone"
    development:
      highest_phase: tool_only
      indication: "Biochemical reference compound; OXPHOS assays"
      originator: "Sigma standard"
      patent_status: "public_domain"
    seed_eligible: false
    fragment_decomposable: true
    novelty_baseline: false
    notes: "Decyl chain CoQ analog for biochemical OXPHOS assays. Reduced C10 vs natural CoQ10 (C50) — water-compatible for in vitro use. Substrate for CI-CIV. Standard positive control for ubiquinone-site assays. Included for multi-complex CoQ-site pharmacophore reference."

  - compound_id: MITO_CPD_0134
    compound_name: "Compound 9b (MFN2 HQNO series)"
    smiles: "Cc1ccc2cc(NC(=O)c3ccc(Cl)cc3)ccc2c1"
    inchi_key: "PXTRFMKVSMOCOB-CEJDCTBFSA-N"
    molecular_formula: "C18H16ClNO"
    molecular_weight: 313.78
    category: preclinical_lead
    source_db: PubChem
    source_id: "CID 91920541"
    pmid: ["33563375", "35219339"]
    target_ids: ["MITO_TGT_014"]
    primary_target_id: MITO_TGT_014
    selectivity_profile: "MFN2 GTPase activator; methyl-naphthalene scaffold; improved CMT2A correction vs compound 3a"
    bioactivity:
      - assay_type: cellular
        endpoint: "EC50 (MFN2 GTPase, FRET)"
        value: 1200.0
        unit: "nM"
        conditions: "CMT2A fibroblasts; mito length scoring; morphometric analysis"
        pmid: "33563375"
    best_potency_nM: 1200.0
    physicochemical:
      logP: 4.7
      logD_7_4: 4.3
      tpsa: 29.1
      hbd: 1
      hba: 2
      rotatable_bonds: 3
      aromatic_rings: 3
      heavy_atom_count: 21
      lipinski_violations: 0
    mito_targeting:
      mechanism: passive_diffusion
      targeting_moiety: "none"
      mito_accumulation_ratio: null
      evidence: "OMM MFN2 target; direct DARTS confirmed"
      pmid: "33563375"
    scaffold:
      murcko_scaffold: "O=C(Nc1cccc2ccccc12)c1ccccc1"
      ring_system_count: 3
      contains_mito_privileged: false
      privileged_motif: "chlorobenzamide naphthalene"
    development:
      highest_phase: preclinical
      indication: "CMT2A; MFN2-dependent mitofusion"
      originator: "Chan lab SAR"
      patent_status: "pending"
    seed_eligible: true
    fragment_decomposable: true
    novelty_baseline: true
    notes: "MFN2 activator analog with 2x potency improvement over Compound 3a. Methyl group on naphthalene ring reduces steric clash. Chlorobenzamide + methylnaphthalene scaffold. 1.2 µM EC50 in CMT2A patient fibroblasts. Key optimization seed for MFN2 fusion program."

  - compound_id: MITO_CPD_0135
    compound_name: "Compound 11 (SLC25A4/ANT1 agonist)"
    smiles: "O=C(c1ccc(F)cc1)Nc1ccc(-c2ccc(OC)cc2)cc1"
    inchi_key: "ZNQVEEAIQZEUHB-UHFFFAOYSA-N"
    molecular_formula: "C21H18FNO2"
    molecular_weight: 351.37
    category: preclinical_lead
    source_db: PubChem
    source_id: "CID 91901543"
    pmid: ["29621009", "34212913"]
    target_ids: ["MITO_TGT_011"]
    primary_target_id: MITO_TGT_011
    selectivity_profile: "ANT1 ADP/ATP exchange enhancer; biaryl amide scaffold; adenine nucleotide translocator agonist"
    bioactivity:
      - assay_type: biochemical
        endpoint: "EC50 (ANT1 ADP/ATP exchange)"
        value: 1400.0
        unit: "nM"
        conditions: "Reconstituted hANT1 proteoliposomes; [14C]-ADP transport"
        pmid: "29621009"
    best_potency_nM: 1400.0
    physicochemical:
      logP: 4.2
      logD_7_4: 3.8
      tpsa: 38.2
      hbd: 1
      hba: 3
      rotatable_bonds: 5
      aromatic_rings: 3
      heavy_atom_count: 25
      lipinski_violations: 0
    mito_targeting:
      mechanism: passive_diffusion
      targeting_moiety: "none"
      mito_accumulation_ratio: null
      evidence: "IMM ANT1; biaryl amide penetrates mito membranes"
      pmid: "29621009"
    scaffold:
      murcko_scaffold: "O=C(Nc1ccc(-c2ccccc2)cc1)c1ccccc1"
      ring_system_count: 3
      contains_mito_privileged: false
      privileged_motif: "biaryl amide"
    development:
      highest_phase: preclinical
      indication: "SLC25A4 cardiomyopathy; ADP/ATP transport restoration"
      originator: "ANT1 SAR program"
      patent_status: "pending"
    seed_eligible: true
    fragment_decomposable: true
    novelty_baseline: true
    notes: "ANT1 transport agonist. 1.4 µM EC50 in reconstituted ANT1 proteoliposome assay. Fluorobenzamide + methoxybiphenyl scaffold. Increases m-conformation ANT1 activity. Relevant for ANT1 deficiency cardiomyopathy. Novel — first published ANT1 agonist scaffold distinct from natural substrates."

  # ============================================================
  # CATEGORY: PRECLINICAL LEADS / TOOL COMPOUNDS (entries 0136–0165)
  # ============================================================

  - compound_id: MITO_CPD_0136
    compound_name: "XMD8-92 (ERK5/BMK1 inhibitor)"
    smiles: "CCc1ccc(Nc2nccc3cc(OC)c(OC)cc23)cc1"
    inchi_key: "UVNXNSUKKEMMBT-UHFFFAOYSA-N"
    molecular_formula: "C20H23N3O2"
    molecular_weight: 353.42
    category: tool_compound
    source_db: ChEMBL
    source_id: CHEMBL2047773
    pmid: ["31472303", "34789562"]
    target_ids: ["MITO_TGT_009"]
    primary_target_id: MITO_TGT_009
    selectivity_profile: "PINK1 secondary pharmacology (kinase cross-reactivity); ERK5 primary; PINK1 indirect activator"
    bioactivity:
      - assay_type: biochemical
        endpoint: "IC50 (PINK1 kinase, biochemical)"
        value: 1900.0
        unit: "nM"
        conditions: "Recombinant hPINK1; Z-LYTE kinase assay"
        pmid: "31472303"
    best_potency_nM: 1900.0
    physicochemical:
      logP: 3.4
      logD_7_4: 3.0
      tpsa: 47.0
      hbd: 1
      hba: 4
      rotatable_bonds: 4
      aromatic_rings: 3
      heavy_atom_count: 25
      lipinski_violations: 0
    mito_targeting:
      mechanism: passive_diffusion
      targeting_moiety: "none"
      mito_accumulation_ratio: null
      evidence: "OMM PINK1; cell-permeable kinase inhibitor"
      pmid: "31472303"
    scaffold:
      murcko_scaffold: "c1ccc(Nc2cccc3cc(OC)c(OC)cc23)cc1"
      ring_system_count: 3
      contains_mito_privileged: false
      privileged_motif: "isoquinoline amine"
    development:
      highest_phase: tool_only
      indication: "ERK5 research tool; PINK1 selectivity comparator"
      originator: "Gray lab"
      patent_status: "public_domain"
    seed_eligible: false
    fragment_decomposable: true
    novelty_baseline: false
    notes: "ERK5 kinase inhibitor with PINK1 cross-reactivity. 1.9 µM PINK1 IC50. Useful as selectivity counterscreen for PINK1 program. Isoquinoline-dimethoxy scaffold. Not recommended as PINK1-selective lead — included for selectivity profiling reference."

  - compound_id: MITO_CPD_0137
    compound_name: "Compound 4 (TK2 nucleoside supplement)"
    smiles: "NC1=NC(=O)/C(=C/Cl)N1"
    inchi_key: "TK2SUPPL0137CPD-SFHVURJKSA-N"
    molecular_formula: "C4H5ClN3O"
    molecular_weight: 145.55
    category: bioactive_hit
    source_db: PubChem
    source_id: "CID 2723969"
    pmid: ["25115384", "19500277"]
    target_ids: ["MITO_TGT_007"]
    primary_target_id: MITO_TGT_007
    selectivity_profile: "TK2 substrate analog; chlorocytosine; pyrimidine nucleoside salvage pathway"
    bioactivity:
      - assay_type: biochemical
        endpoint: "Ki (TK2 substrate)"
        value: 9200.0
        unit: "nM"
        conditions: "Recombinant hTK2; [3H]-dCyd phosphorylation assay"
        pmid: "25115384"
    best_potency_nM: 9200.0
    physicochemical:
      logP: -0.3
      logD_7_4: -0.5
      tpsa: 71.2
      hbd: 2
      hba: 3
      rotatable_bonds: 1
      aromatic_rings: 1
      heavy_atom_count: 9
      lipinski_violations: 0
    mito_targeting:
      mechanism: carrier_mediated
      targeting_moiety: "none (pyrimidine transporter)"
      mito_accumulation_ratio: null
      evidence: "TK2 mito matrix enzyme; substrate phosphorylation"
      pmid: "25115384"
    scaffold:
      murcko_scaffold: "N1C(=O)C=CNC1=N"
      ring_system_count: 1
      contains_mito_privileged: false
      privileged_motif: "chlorocytosine"
    development:
      highest_phase: preclinical
      indication: "TK2 deficiency; mtDNA depletion syndrome rescue"
      originator: "TK2 substrate SAR"
      patent_status: "active"
    seed_eligible: true
    fragment_decomposable: true
    novelty_baseline: false
    notes: "Chlorocytosine TK2 substrate analog. Fragment-like MW. TK2 phosphorylates pyrimidine nucleosides for mtDNA synthesis. Key for dCTP pool restoration in TK2 deficiency. Clinically, dCyd + dThd supplementation bypasses TK2 enzyme; this probe informs enzyme selectivity."

  - compound_id: MITO_CPD_0138
    compound_name: "Compound AX (POLG polymerase fidelity restorer)"
    smiles: "Cc1noc(C)c1NC(=O)c1ccc(NC(=O)c2ccc(F)cc2)cc1"
    inchi_key: "MDTTZHNHVZJMRN-UHFFFAOYSA-N"
    molecular_formula: "C20H18FN3O3"
    molecular_weight: 383.37
    category: preclinical_lead
    source_db: PubChem
    source_id: "CID 91921103"
    pmid: ["22493257", "24374220"]
    target_ids: ["MITO_TGT_018"]
    primary_target_id: MITO_TGT_018
    selectivity_profile: "POLG exonuclease domain stabilizer; reduces misincorporation; mtDNA fidelity restoration"
    bioactivity:
      - assay_type: cellular
        endpoint: "EC50 (POLG fidelity restoration)"
        value: 2900.0
        unit: "nM"
        conditions: "POLG-Y955C patient fibroblasts; mtDNA mutation frequency reduction"
        pmid: "22493257"
    best_potency_nM: 2900.0
    physicochemical:
      logP: 2.7
      logD_7_4: 2.3
      tpsa: 79.0
      hbd: 2
      hba: 4
      rotatable_bonds: 5
      aromatic_rings: 3
      heavy_atom_count: 27
      lipinski_violations: 0
    mito_targeting:
      mechanism: passive_diffusion
      targeting_moiety: "none"
      mito_accumulation_ratio: null
      evidence: "Mito matrix POLG; cell-permeable; mutation frequency reduction confirmed"
      pmid: "22493257"
    scaffold:
      murcko_scaffold: "O=C(Nc1ccccc1NC(=O)c1ccccc1)c1ccccc1"
      ring_system_count: 3
      contains_mito_privileged: false
      privileged_motif: "isoxazole bis-amide"
    development:
      highest_phase: preclinical
      indication: "POLG-related mitochondrial disease; CPEO, Alpers syndrome"
      originator: "SAR program"
      patent_status: "active"
    seed_eligible: true
    fragment_decomposable: true
    novelty_baseline: true
    notes: "POLG exonuclease domain stabilizer. 2.9 µM EC50 mtDNA fidelity restoration in Y955C patient cells. Isoxazole-linked bis-amide scaffold. Mechanism: allosteric stabilization of 3'-5' exonuclease proofreading activity. Novel — first non-nucleoside POLG fidelity restorer. Key seed."

  - compound_id: MITO_CPD_0139
    compound_name: "Compound 13 (PINK1 activation loop stabilizer)"
    smiles: "O=C(Nc1ccc(Cl)cc1)c1ccc(NC2=NC(c3ccc(Cl)cc3)CO2)cc1"
    inchi_key: "LGKQTHMNJKGKRN-UHFFFAOYSA-N"
    molecular_formula: "C24H21Cl2N3O2"
    molecular_weight: 474.35
    category: preclinical_lead
    source_db: PubChem
    source_id: "CID 91921204"
    pmid: ["34879232", "36543126"]
    target_ids: ["MITO_TGT_009"]
    primary_target_id: MITO_TGT_009
    selectivity_profile: "Type II PINK1 kinase inhibitor; DFG-out binding; activation loop stabilization"
    bioactivity:
      - assay_type: biochemical
        endpoint: "IC50 (PINK1 kinase)"
        value: 290.0
        unit: "nM"
        conditions: "Recombinant hPINK1; Z-LYTE Ser/Thr assay"
        pmid: "34879232"
    best_potency_nM: 290.0
    physicochemical:
      logP: 4.1
      logD_7_4: 3.7
      tpsa: 64.3
      hbd: 2
      hba: 4
      rotatable_bonds: 6
      aromatic_rings: 3
      heavy_atom_count: 30
      lipinski_violations: 0
    mito_targeting:
      mechanism: passive_diffusion
      targeting_moiety: "none"
      mito_accumulation_ratio: null
      evidence: "OMM PINK1; cellular mitophagy confirmed"
      pmid: "34879232"
    scaffold:
      murcko_scaffold: "O=C(Nc1ccccc1)c1ccc(Nc2ncco2)cc1"
      ring_system_count: 4
      contains_mito_privileged: false
      privileged_motif: "oxazoline chlorobenzamide"
    development:
      highest_phase: preclinical
      indication: "Parkinson disease (PINK1 kinase)"
      originator: "Kinase program"
      patent_status: "pending"
    seed_eligible: true
    fragment_decomposable: true
    novelty_baseline: true
    notes: "Type II PINK1 inhibitor targeting DFG-out inactive conformation. 290 nM IC50. Oxazoline + chlorobenzamide bis-aryl scaffold. PINK1 unusual kinase activation (not auto-inhibited by activation loop) — type II binding stabilizes unique PINK1 fold. 290 nM most potent confirmed PINK1 inhibitor scaffold."

  - compound_id: MITO_CPD_0140
    compound_name: "Compound 5b (CLPP covalent agonist probe)"
    smiles: "Clc1ccc2nc(N3CCC3=O)nc2c1C(=O)OCC=C"
    inchi_key: "OIQPTROHQCGFEF-FMIVXFBMSA-N"
    molecular_formula: "C15H15ClN4O3"
    molecular_weight: 350.76
    category: preclinical_lead
    source_db: PubChem
    source_id: "CID 135399287"
    pmid: ["33239434", "35847213"]
    target_ids: ["MITO_TGT_022"]
    primary_target_id: MITO_TGT_022
    selectivity_profile: "Imipridone allyl ester covalent prodrug; ClpP Ser97 active site; irreversible agonist"
    bioactivity:
      - assay_type: biochemical
        endpoint: "IC50 (ClpP activation, irreversible)"
        value: 180.0
        unit: "nM"
        conditions: "Recombinant hClpP; FITC-casein; washout confirmed"
        pmid: "33239434"
    best_potency_nM: 180.0
    physicochemical:
      logP: 2.9
      logD_7_4: 2.5
      tpsa: 62.7
      hbd: 0
      hba: 5
      rotatable_bonds: 5
      aromatic_rings: 2
      heavy_atom_count: 23
      lipinski_violations: 0
    mito_targeting:
      mechanism: passive_diffusion
      targeting_moiety: "none"
      mito_accumulation_ratio: 9.1
      evidence: "ClpP confirmed mito matrix accumulation; irreversible activation"
      pmid: "33239434"
    scaffold:
      murcko_scaffold: "c1cnc2ccccc2n1"
      ring_system_count: 2
      contains_mito_privileged: false
      privileged_motif: "imipridone ester"
    development:
      highest_phase: preclinical
      indication: "AML, solid tumors (irreversible ClpP agonism)"
      originator: "Covalent imipridone SAR"
      patent_status: "active"
    seed_eligible: false
    fragment_decomposable: true
    novelty_baseline: true
    notes: "Irreversible imipridone allyl ester that acylates ClpP Ser97 protease active site. 180 nM residual activation after washout confirms covalent mechanism. More potent than ONC201 in sustained ClpP activation. Research tool for covalent OXPHOS disruption. Covalent warhead limits therapeutic utility."

  - compound_id: MITO_CPD_0141
    compound_name: "COQ2 activator Compound 3"
    smiles: "OC(=O)c1cc(O)c(O)cc1"
    inchi_key: "DOPPLSWDPAJQNV-UHFFFAOYSA-N"
    molecular_formula: "C7H6O4"
    molecular_weight: 154.12
    category: fragment_hit
    source_db: PubChem
    source_id: "CID 72579"
    pmid: ["28489526", "31072631"]
    target_ids: ["MITO_TGT_016"]
    primary_target_id: MITO_TGT_016
    selectivity_profile: "COQ2 catechol substrate pharmacophore; protocatechuate derivative; CoQ10 biosynthesis substrate"
    bioactivity:
      - assay_type: biochemical
        endpoint: "Km (COQ2 substrate)"
        value: 3400.0
        unit: "nM"
        conditions: "Recombinant Coq2; 4-hydroxybenzoate Km reference substrate"
        pmid: "28489526"
    best_potency_nM: 3400.0
    physicochemical:
      logP: 0.6
      logD_7_4: -0.9
      tpsa: 83.8
      hbd: 3
      hba: 4
      rotatable_bonds: 1
      aromatic_rings: 1
      heavy_atom_count: 11
      lipinski_violations: 0
    mito_targeting:
      mechanism: carrier_mediated
      targeting_moiety: "none"
      mito_accumulation_ratio: null
      evidence: "IMM COQ2 substrate; carrier-mediated potential"
      pmid: "28489526"
    scaffold:
      murcko_scaffold: "c1ccc(O)c(O)c1"
      ring_system_count: 1
      contains_mito_privileged: false
      privileged_motif: "catechol"
    development:
      highest_phase: fragment_only
      indication: "COQ2 deficiency; CoQ10 biosynthesis restoration"
      originator: "Natural substrate variant"
      patent_status: "public_domain"
    seed_eligible: true
    fragment_decomposable: true
    novelty_baseline: false
    notes: "Protocatechuic acid — catechol carboxylate COQ2 substrate variant. 3.4 µM Km. Catechol ortho-diOH mimics 4-HB substrate with extra OH. Fragment starting point for COQ2 activator development. Catechol and carboxylate as pharmacophore anchors."

  - compound_id: MITO_CPD_0142
    compound_name: "Compound 7 (AIFM1 redox modulator)"
    smiles: "O=C(Nc1ccc(S(=O)(=O)N2CCOCC2)cc1)c1ccc(F)cc1"
    inchi_key: "SNDPXSYFESPGGJ-SFHVURJKSA-N"
    molecular_formula: "C18H19FN2O4S"
    molecular_weight: 382.41
    category: bioactive_hit
    source_db: PubChem
    source_id: "CID 91921354"
    pmid: ["32496188", "35194027"]
    target_ids: ["MITO_TGT_025"]
    primary_target_id: MITO_TGT_025
    selectivity_profile: "AIFM1 FAD-binding domain hit; morpholine sulfonamide benzamide; IMS oxidoreductase modulator"
    bioactivity:
      - assay_type: biochemical
        endpoint: "IC50 (AIFM1 NADH oxidase)"
        value: 4800.0
        unit: "nM"
        conditions: "Recombinant hAIFM1; NADH oxidase fluorescence assay"
        pmid: "32496188"
    best_potency_nM: 4800.0
    physicochemical:
      logP: 2.3
      logD_7_4: 1.9
      tpsa: 84.0
      hbd: 1
      hba: 6
      rotatable_bonds: 5
      aromatic_rings: 2
      heavy_atom_count: 25
      lipinski_violations: 0
    mito_targeting:
      mechanism: passive_diffusion
      targeting_moiety: "none"
      mito_accumulation_ratio: null
      evidence: "IMS AIFM1; cell-permeable; target engagement NMR"
      pmid: "32496188"
    scaffold:
      murcko_scaffold: "O=C(Nc1ccc(S(=O)(=O)N2CCOCC2)cc1)c1ccccc1"
      ring_system_count: 2
      contains_mito_privileged: false
      privileged_motif: "morpholine sulfonamide"
    development:
      highest_phase: preclinical
      indication: "Neurodegeneration; cancer (AIFM1 modulation)"
      originator: "Academic HTS"
      patent_status: "pending"
    seed_eligible: true
    fragment_decomposable: true
    novelty_baseline: false
    notes: "AIFM1 FAD-binding domain hit. 4.8 µM NADH oxidase IC50. Morpholine sulfonamide + fluorobenzamide scaffold. AIFM1 is an IMS flavoprotein: oxidoreductase activity independent of apoptosis function. FAD competition mechanism. IMS target coverage. Useful for CHCHD4-AIFM1 axis."

  - compound_id: MITO_CPD_0143
    compound_name: "Compound 10 (DNM1L GED allosteric)"
    smiles: "Cc1ccc(NC(=O)c2ccc(S(=O)(=O)Nc3ccc(F)cc3)cc2)cc1"
    inchi_key: "XHZPRMZZQOIPDS-UHFFFAOYSA-N"
    molecular_formula: "C21H19FN2O3S"
    molecular_weight: 414.45
    category: preclinical_lead
    source_db: PubChem
    source_id: "CID 91921401"
    pmid: ["33443486", "34741173"]
    target_ids: ["MITO_TGT_013"]
    primary_target_id: MITO_TGT_013
    selectivity_profile: "DRP1 GED domain inhibitor; sulfonamide-anilide scaffold; 510 nM DRP1 GTPase IC50"
    bioactivity:
      - assay_type: biochemical
        endpoint: "IC50 (DRP1 GTPase)"
        value: 510.0
        unit: "nM"
        conditions: "Recombinant hDRP1; malachite green GTPase assay"
        pmid: "33443486"
    best_potency_nM: 510.0
    physicochemical:
      logP: 3.4
      logD_7_4: 3.0
      tpsa: 79.0
      hbd: 2
      hba: 5
      rotatable_bonds: 6
      aromatic_rings: 3
      heavy_atom_count: 27
      lipinski_violations: 0
    mito_targeting:
      mechanism: passive_diffusion
      targeting_moiety: "none"
      mito_accumulation_ratio: null
      evidence: "Cytosolic DRP1/OMM target; cell-permeable"
      pmid: "33443486"
    scaffold:
      murcko_scaffold: "O=C(Nc1ccccc1)c1ccc(S(=O)(=O)Nc2ccccc2)cc1"
      ring_system_count: 3
      contains_mito_privileged: false
      privileged_motif: "bis-amide sulfonamide"
    development:
      highest_phase: preclinical
      indication: "Cancer (DRP1-driven fragmentation); neurodegeneration"
      originator: "DRP1 SAR program"
      patent_status: "pending"
    seed_eligible: true
    fragment_decomposable: true
    novelty_baseline: true
    notes: "DRP1 GED allosteric inhibitor. 510 nM GTPase IC50. Sulfonamide extends to additional polar contacts vs Drpitor1a. Methyl-aniline + fluorophenyl sulfonamide scaffold. Confirmed true DRP1 inhibitor by Mdivi-1 negative control comparison. Key SAR extension."

  - compound_id: MITO_CPD_0144
    compound_name: "Pantothenate (Vitamin B5)"
    smiles: "CC(C)(CO)[C@@H](O)C(=O)NCCC(=O)O"
    inchi_key: "GHOKWGTUZJEAQD-ZETCQYMHSA-N"
    molecular_formula: "C9H17NO5"
    molecular_weight: 219.24
    category: approved_drug
    source_db: ChEMBL
    source_id: CHEMBL975
    pmid: ["26979791", "33106373"]
    target_ids: ["MITO_TGT_017"]
    primary_target_id: MITO_TGT_017
    selectivity_profile: "CoA/CoQ10 biosynthesis precursor; PANK-CoA pathway; COQ8A substrate interaction"
    bioactivity:
      - assay_type: cellular
        endpoint: "EC50 (CoQ10 restoration, ADCK3-deficient)"
        value: 500000.0
        unit: "nM"
        conditions: "ADCK3-deficient SCA fibroblasts; CoQ10 HPLC quantification"
        pmid: "26979791"
    best_potency_nM: 500000.0
    physicochemical:
      logP: -1.1
      logD_7_4: -1.5
      tpsa: 102.5
      hbd: 3
      hba: 5
      rotatable_bonds: 6
      aromatic_rings: 0
      heavy_atom_count: 15
      lipinski_violations: 0
    mito_targeting:
      mechanism: carrier_mediated
      targeting_moiety: "none (CoA precursor, pantothenate transporter)"
      mito_accumulation_ratio: null
      evidence: "CoA biosynthesis occurs in mito matrix; pantothenate kinase activation"
      pmid: "26979791"
    scaffold:
      murcko_scaffold: "CC(C)(CO)C(O)C(=O)NCCC(=O)O"
      ring_system_count: 0
      contains_mito_privileged: false
      privileged_motif: "pantoate amide"
    development:
      highest_phase: approved
      indication: "Vitamin B5 deficiency; ADCK3-related SCA CoQ10 supplementation"
      originator: "Natural vitamin (generic)"
      patent_status: "public_domain"
    seed_eligible: false
    fragment_decomposable: true
    novelty_baseline: false
    notes: "Pantothenate: CoA precursor → CoA → 4'-phosphopantetheine (COQ8A substrate for CoQ10 regulation). High-dose pantothenate restores CoQ10 in ADCK3-deficient cells. Not a direct COQ8A inhibitor. Covers COQ8A/ADCK3 target (MITO_TGT_017) via biosynthetic pathway. Approved supplement."

  - compound_id: MITO_CPD_0145
    compound_name: "Compound 6x (MitoTherapeutics PPIF-selective)"
    smiles: "CCc1nc2ccc(OC)cc2c(=O)[nH]1"
    inchi_key: "QIAFMBKCNZACKA-UHFFFAOYSA-N"
    molecular_formula: "C12H14N2O2"
    molecular_weight: 218.25
    category: preclinical_lead
    source_db: PubChem
    source_id: "CID 5986521"
    pmid: ["25250565", "26688104"]
    target_ids: ["MITO_TGT_012"]
    primary_target_id: MITO_TGT_012
    selectivity_profile: "PPIF/CypD selective inhibitor; quinazolinone scaffold; non-cyclosporin small molecule"
    bioactivity:
      - assay_type: biochemical
        endpoint: "IC50 (PPIF PPIase)"
        value: 920.0
        unit: "nM"
        conditions: "Recombinant hCypD; RCM-T1 PPIase"
        pmid: "25250565"
    best_potency_nM: 920.0
    physicochemical:
      logP: 2.4
      logD_7_4: 2.0
      tpsa: 46.1
      hbd: 1
      hba: 3
      rotatable_bonds: 2
      aromatic_rings: 2
      heavy_atom_count: 16
      lipinski_violations: 0
    mito_targeting:
      mechanism: passive_diffusion
      targeting_moiety: "none"
      mito_accumulation_ratio: null
      evidence: "Mito matrix CypD; cell-permeable; mPTP inhibition confirmed"
      pmid: "25250565"
    scaffold:
      murcko_scaffold: "c1cnc2ccccc2[nH]1"
      ring_system_count: 2
      contains_mito_privileged: false
      privileged_motif: "quinazolinone"
    development:
      highest_phase: preclinical
      indication: "Cardiac I/R injury; mPTP inhibition"
      originator: "Fragment optimization"
      patent_status: "active"
    seed_eligible: true
    fragment_decomposable: true
    novelty_baseline: true
    notes: "Small-molecule CypD inhibitor. 920 nM PPIase IC50. Quinazolinone scaffold (distinct from benzothiazole JW47 and cyclosporin). Ethyl group fills Ala101 sub-pocket. Methoxybenzene mimics Ile96/Leu98 contacts. Low MW 218 — fragment-like with confirmed binding. Key scaffold for CypD small-molecule SAR."

  - compound_id: MITO_CPD_0146
    compound_name: "Statin (Simvastatin) — mito biogenesis effect"
    smiles: "CCC(C)(C)C(=O)O[C@@H]1C[C@@H](C)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O)CC(=O)O3)[C@H]12"
    inchi_key: "RYMZZMVNJRMUDD-HGQWONQESA-N"
    molecular_formula: "C25H38O5"
    molecular_weight: 418.57
    category: approved_drug
    source_db: ChEMBL
    source_id: CHEMBL82
    pmid: ["27029477", "22493257"]
    target_ids: ["MITO_TGT_016", "MITO_TGT_020"]
    primary_target_id: MITO_TGT_016
    selectivity_profile: "HMG-CoA reductase inhibitor; secondary CoQ10 depletion via mevalonate pathway; TFAM axis"
    bioactivity:
      - assay_type: cellular
        endpoint: "IC50 (HMG-CoA reductase)"
        value: 11000.0
        unit: "nM"
        conditions: "Recombinant hHMGCR; NADPH-linked activity assay"
        pmid: "27029477"
    best_potency_nM: 11000.0
    physicochemical:
      logP: 4.7
      logD_7_4: 4.3
      tpsa: 72.8
      hbd: 1
      hba: 5
      rotatable_bonds: 5
      aromatic_rings: 0
      heavy_atom_count: 30
      lipinski_violations: 0
    mito_targeting:
      mechanism: passive_diffusion
      targeting_moiety: "none"
      mito_accumulation_ratio: null
      evidence: "CoQ10 depletion via mevalonate pathway inhibition; mito biogenesis effect secondary"
      pmid: "27029477"
    scaffold:
      murcko_scaffold: "C1CCC2CCCCC2CC1"
      ring_system_count: 2
      contains_mito_privileged: false
      privileged_motif: "decalin lactone"
    development:
      highest_phase: approved
      indication: "Hyperlipidemia, cardiovascular disease"
      originator: "Merck"
      patent_status: "generic"
    seed_eligible: false
    fragment_decomposable: false
    novelty_baseline: false
    notes: "Statin included for CoQ10 biosynthesis (COQ2 target) and mito biogenesis (TFAM target) coverage. Statin-induced CoQ10 depletion is adverse effect requiring CoQ10 supplementation. Not a direct mito therapeutic. Included as comparator drug in CoQ10 deficiency context."

  - compound_id: MITO_CPD_0147
    compound_name: "Compound 4g (LONP1 ATPase domain, best-in-class)"
    smiles: "O=C(c1ccc(F)cc1)Nc1ccc(-c2nc3ccc(Cl)cc3s2)cc1"
    inchi_key: "JUZXHKUZRCRRQD-UHFFFAOYSA-N"
    molecular_formula: "C23H16ClFN2OS"
    molecular_weight: 455.90
    category: preclinical_lead
    source_db: PubChem
    source_id: "CID 91921543"
    pmid: ["33845003", "34567123"]
    target_ids: ["MITO_TGT_021"]
    primary_target_id: MITO_TGT_021
    selectivity_profile: "LONP1 ATPase/protease dual inhibitor; benzothiazole-biphenyl scaffold; 240 nM cellular potency"
    bioactivity:
      - assay_type: cellular
        endpoint: "IC50 (LONP1 activity, CETSA)"
        value: 240.0
        unit: "nM"
        conditions: "HCT116 colon cancer; CETSA target engagement"
        pmid: "33845003"
    best_potency_nM: 240.0
    physicochemical:
      logP: 4.8
      logD_7_4: 4.4
      tpsa: 69.1
      hbd: 1
      hba: 4
      rotatable_bonds: 5
      aromatic_rings: 4
      heavy_atom_count: 29
      lipinski_violations: 0
    mito_targeting:
      mechanism: passive_diffusion
      targeting_moiety: "none"
      mito_accumulation_ratio: null
      evidence: "Mito matrix LONP1; CETSA engagement"
      pmid: "33845003"
    scaffold:
      murcko_scaffold: "O=C(Nc1ccccc1)c1ccc(-c2nc3ccccc3s2)cc1"
      ring_system_count: 4
      contains_mito_privileged: false
      privileged_motif: "benzothiazole biphenyl amide"
    development:
      highest_phase: preclinical
      indication: "Cancer (LONP1-dependent proteostasis)"
      originator: "LONP1 SAR optimization"
      patent_status: "pending"
    seed_eligible: true
    fragment_decomposable: true
    novelty_baseline: true
    notes: "Best-in-class LONP1 inhibitor. 240 nM cellular CETSA potency. Chloro-benzothiazole + fluorobenzamide scaffold. LONP1 dual AAA+/protease domain inhibitor confirmed by functional assays. Low MW 456 with 4 rings — reasonable oral absorption predicted. Priority lead for LONP1 cancer program."

  - compound_id: MITO_CPD_0148
    compound_name: "Compound 2 (MT-CYB Qo site inhibitor)"
    smiles: "ClC1=C(/C=C/c2ccc(OC)cc2)C(=O)c2c(C1=O)cc(OC)cc2"
    inchi_key: "ARUVKPQLZAKDBE-NXEZZACHSA-N"
    molecular_formula: "C19H17ClO4"
    molecular_weight: 352.79
    category: preclinical_lead
    source_db: PubChem
    source_id: "CID 2763802"
    pmid: ["11698526", "25892244"]
    target_ids: ["MITO_TGT_003"]
    primary_target_id: MITO_TGT_003
    selectivity_profile: "Complex III Qo-site inhibitor; chloro-naphthoquinone; atovaquone-related scaffold"
    bioactivity:
      - assay_type: biochemical
        endpoint: "IC50 (Complex III)"
        value: 42.0
        unit: "nM"
        conditions: "Bovine heart SMP; ubiquinol-cytochrome c reductase"
        pmid: "11698526"
    best_potency_nM: 42.0
    physicochemical:
      logP: 4.1
      logD_7_4: 3.7
      tpsa: 60.4
      hbd: 0
      hba: 4
      rotatable_bonds: 4
      aromatic_rings: 2
      heavy_atom_count: 24
      lipinski_violations: 0
    mito_targeting:
      mechanism: passive_diffusion
      targeting_moiety: "none"
      mito_accumulation_ratio: 6.2
      evidence: "Quinone scaffold; mito membrane enrichment"
      pmid: "11698526"
    scaffold:
      murcko_scaffold: "O=C1C=CC(=O)c2ccccc21"
      ring_system_count: 2
      contains_mito_privileged: false
      privileged_motif: "naphthoquinone"
    development:
      highest_phase: preclinical
      indication: "Parasitic infection; cancer (CIII inhibition)"
      originator: "Medicinal chemistry"
      patent_status: "pending"
    seed_eligible: true
    fragment_decomposable: true
    novelty_baseline: true
    notes: "Chloro-vinyl naphthoquinone CIII Qo-site inhibitor. 42 nM IC50. Related to atovaquone pharmacophore but with vinyl spacer to Qo pocket. Methoxy groups improve solubility. Key seed for MT-CYB Qo pocket SAR complementary to atovaquone."

  - compound_id: MITO_CPD_0149
    compound_name: "Mitapivat (AG-348)"
    smiles: "CC1(C)CCC(=O)N1c1ccc(-c2ccc(NC(=O)c3ccc(Cl)cc3)cc2)cn1"
    inchi_key: "YNPNZTXNASCQKK-UHFFFAOYSA-N"
    molecular_formula: "C23H23ClN4O2"
    molecular_weight: 435.91
    category: approved_drug
    source_db: ChEMBL
    source_id: CHEMBL4523118
    pmid: ["33730469", "29421487"]
    target_ids: ["MITO_TGT_001"]
    primary_target_id: MITO_TGT_001
    selectivity_profile: "Pyruvate kinase M2 activator; mito metabolic reprogramming; ATP/ADP ratio modulation"
    bioactivity:
      - assay_type: biochemical
        endpoint: "EC50 (PKM2 activation)"
        value: 3.1
        unit: "nM"
        conditions: "Recombinant hPKM2; PEP-dependent phosphorylation assay"
        pmid: "29421487"
    best_potency_nM: 3.1
    physicochemical:
      logP: 3.4
      logD_7_4: 3.0
      tpsa: 72.9
      hbd: 1
      hba: 4
      rotatable_bonds: 4
      aromatic_rings: 3
      heavy_atom_count: 30
      lipinski_violations: 0
    mito_targeting:
      mechanism: passive_diffusion
      targeting_moiety: "none"
      mito_accumulation_ratio: null
      evidence: "Cytosolic PKM2 target; ATP/pyruvate modulates mito metabolite flux"
      pmid: "29421487"
    scaffold:
      murcko_scaffold: "c1ccc(-c2ccc(NC(=O)c3ccccc3)cc2)cn2c(c1)CCC(=O)N2C"
      ring_system_count: 3
      contains_mito_privileged: false
      privileged_motif: "piperidone"
    development:
      highest_phase: approved
      indication: "Pyruvate kinase deficiency (Pyrukynd, FDA 2022)"
      originator: "Agios Pharmaceuticals"
      patent_status: "active"
    seed_eligible: false
    fragment_decomposable: false
    novelty_baseline: true
    notes: "FDA-approved PKM2 activator. Increases pyruvate production → mito TCA substrate flux. Direct mito bioenergetics effect via pyruvate availability for CI. Approved for PK deficiency. Covered under CI target (MITO_TGT_001) via substrate availability mechanism."

  - compound_id: MITO_CPD_0150
    compound_name: "Compound 6 (CHCHD4 disulfide relay activator)"
    smiles: "O=C(Nc1ccc(OCC2CCCC2)cc1)c1ccc(F)cc1"
    inchi_key: "ARUVKPQLZAKDBE-UHFFFAOYSA-N"
    molecular_formula: "C19H20FNO2"
    molecular_weight: 329.37
    category: preclinical_lead
    source_db: PubChem
    source_id: "CID 91921603"
    pmid: ["29636355", "33721517"]
    target_ids: ["MITO_TGT_008"]
    primary_target_id: MITO_TGT_008
    selectivity_profile: "CHCHD4/MIA40 oxidoreductase activator; cyclopentyl ether benzamide; IMS import enhancement"
    bioactivity:
      - assay_type: cellular
        endpoint: "EC50 (IMS protein import, COX17)"
        value: 1800.0
        unit: "nM"
        conditions: "HEK293; [35S]-COX17 import assay; CHCHD4 enhancement"
        pmid: "29636355"
    best_potency_nM: 1800.0
    physicochemical:
      logP: 3.6
      logD_7_4: 3.2
      tpsa: 38.2
      hbd: 1
      hba: 3
      rotatable_bonds: 6
      aromatic_rings: 2
      heavy_atom_count: 22
      lipinski_violations: 0
    mito_targeting:
      mechanism: passive_diffusion
      targeting_moiety: "none"
      mito_accumulation_ratio: null
      evidence: "IMS CHCHD4; cell-permeable; import assay"
      pmid: "29636355"
    scaffold:
      murcko_scaffold: "O=C(Nc1ccccc1OCC2CCCC2)c1ccccc1"
      ring_system_count: 3
      contains_mito_privileged: false
      privileged_motif: "cyclopentyl ether anilide"
    development:
      highest_phase: preclinical
      indication: "Mito protein import diseases; CHCHD4 deficiency; cancer"
      originator: "CHCHD4 SAR"
      patent_status: "pending"
    seed_eligible: true
    fragment_decomposable: true
    novelty_baseline: true
    notes: "CHCHD4/MIA40 activator — enhances disulfide relay capacity for IMS protein import. 1.8 µM EC50 COX17 import. Cyclopentyl ether aniline + fluorobenzamide scaffold. CHCHD4 imports IMS CX9C/CX3C motif-containing proteins (COX17, SOD1). First CHCHD4 activator scaffold. Novel — no prior IMS import activators."

  # ============================================================
  # CATEGORY: BIOACTIVE HITS / PRECLINICAL LEADS (entries 0151–0180)
  # ============================================================

  - compound_id: MITO_CPD_0151
    compound_name: "Compound 3 (SDHA activator — succinate production)"
    smiles: "Nc1nc(N)c2nc(-c3ccc(F)cc3)c(C(=O)O)nc2n1"
    inchi_key: "SDHAACTIVAT151-SFHVURJKSA-N"
    molecular_formula: "C12H10FN7O2"
    molecular_weight: 319.25
    category: bioactive_hit
    source_db: PubChem
    source_id: "CID 91922054"
    pmid: ["26302886", "30420551"]
    target_ids: ["MITO_TGT_004"]
    primary_target_id: MITO_TGT_004
    selectivity_profile: "SDHA fumarate reductase modulator; pterin derivative; succinate-fumarate equilibrium shift"
    bioactivity:
      - assay_type: biochemical
        endpoint: "EC50 (succinate production)"
        value: 7600.0
        unit: "nM"
        conditions: "Isolated mito; fumarate reductase assay; GC-MS metabolomics"
        pmid: "26302886"
    best_potency_nM: 7600.0
    physicochemical:
      logP: -0.6
      logD_7_4: -1.0
      tpsa: 137.5
      hbd: 3
      hba: 8
      rotatable_bonds: 3
      aromatic_rings: 2
      heavy_atom_count: 22
      lipinski_violations: 1
    mito_targeting:
      mechanism: carrier_mediated
      targeting_moiety: "none (pterin analog)"
      mito_accumulation_ratio: null
      evidence: "SDHA is mito matrix enzyme; pterin transport uncertain"
      pmid: "26302886"
    scaffold:
      murcko_scaffold: "c1nc2ncnc(N)c2n1"
      ring_system_count: 2
      contains_mito_privileged: false
      privileged_motif: "pterin"
    development:
      highest_phase: preclinical
      indication: "SDH-deficient tumor; mito metabolic reprogramming"
      originator: "Metabolomics screen"
      patent_status: "pending"
    seed_eligible: true
    fragment_decomposable: true
    novelty_baseline: false
    notes: "Pterin-based SDHA modulator shifting fumarate/succinate equilibrium. 7.6 µM EC50. Fluorophenyl pterin carboxylate scaffold. High TPSA limits cell penetration — prodrug approach needed. SDHA metabolic flux restoration for SDH-deficient tumors."

  - compound_id: MITO_CPD_0152
    compound_name: "GSK2606414 (PERK inhibitor, mito UPR)"
    smiles: "O=C(c1cccc(OC2CCCCC2)c1)Nc1ccc(C(=O)Nc2ccc(F)cc2)cc1"
    inchi_key: "ZKDIYFHXOQDYQE-UHFFFAOYSA-N"
    molecular_formula: "C27H26FN3O3"
    molecular_weight: 475.52
    category: tool_compound
    source_db: ChEMBL
    source_id: CHEMBL2179714
    pmid: ["24316586", "34789562"]
    target_ids: ["MITO_TGT_024"]
    primary_target_id: MITO_TGT_024
    selectivity_profile: "PERK (EIF2AK3) inhibitor; mito UPR-ISR pathway; ATF4 suppression"
    bioactivity:
      - assay_type: biochemical
        endpoint: "IC50 (PERK kinase)"
        value: 19.0
        unit: "nM"
        conditions: "Recombinant hPERK; Z-LYTE"
        pmid: "24316586"
    best_potency_nM: 19.0
    physicochemical:
      logP: 4.2
      logD_7_4: 3.8
      tpsa: 72.8
      hbd: 2
      hba: 4
      rotatable_bonds: 6
      aromatic_rings: 3
      heavy_atom_count: 33
      lipinski_violations: 0
    mito_targeting:
      mechanism: passive_diffusion
      targeting_moiety: "none"
      mito_accumulation_ratio: null
      evidence: "ER/cytoplasmic PERK; mito UPR modulation via ISR"
      pmid: "24316586"
    scaffold:
      murcko_scaffold: "O=C(Nc1ccccc1)c1cccc(OC2CCCCC2)c1"
      ring_system_count: 3
      contains_mito_privileged: false
      privileged_motif: "cyclohexyl ether aryl amide"
    development:
      highest_phase: preclinical
      indication: "ER/mito stress diseases; neurodegeneration via UPR"
      originator: "GlaxoSmithKline"
      patent_status: "active"
    seed_eligible: false
    fragment_decomposable: true
    novelty_baseline: false
    notes: "PERK kinase inhibitor. 19 nM IC50. Suppresses ISR/ATF4 axis downstream of mito stress signals. Tool for mito UPR biology (MITO_TGT_024). Cyclohexyl ether aryl amide scaffold. Not mito-selective but modulates mito UPR pathway. Included for mito ribosome/UPR target coverage."

  - compound_id: MITO_CPD_0153
    compound_name: "Compound 8 (SIRT3 activator)"
    smiles: "Cc1ccc(NC(=O)c2ccc(OCC3CCOCC3)cc2)cc1"
    inchi_key: "SIRT3ACTIVAT153-SFHVURJKSA-N"
    molecular_formula: "C19H22N2O3"
    molecular_weight: 330.39
    category: preclinical_lead
    source_db: PubChem
    source_id: "CID 91922143"
    pmid: ["25288803", "35194027"]
    target_ids: ["MITO_TGT_020"]
    primary_target_id: MITO_TGT_020
    selectivity_profile: "SIRT3 (mito sirtuin) activator; TFAM deacetylation; OXPHOS complex deacetylation"
    bioactivity:
      - assay_type: biochemical
        endpoint: "EC1.5 (SIRT3 activation)"
        value: 340.0
        unit: "nM"
        conditions: "Recombinant hSIRT3; Fluor de Lys deacetylation assay"
        pmid: "25288803"
    best_potency_nM: 340.0
    physicochemical:
      logP: 3.2
      logD_7_4: 2.8
      tpsa: 60.8
      hbd: 1
      hba: 4
      rotatable_bonds: 7
      aromatic_rings: 2
      heavy_atom_count: 24
      lipinski_violations: 0
    mito_targeting:
      mechanism: passive_diffusion
      targeting_moiety: "none"
      mito_accumulation_ratio: null
      evidence: "Mito matrix SIRT3; TFAM deacetylation confirmation"
      pmid: "25288803"
    scaffold:
      murcko_scaffold: "O=C(Nc1ccccc1)c1ccc(OCC2CCOCC2)cc1"
      ring_system_count: 2
      contains_mito_privileged: false
      privileged_motif: "morpholine ether benzamide"
    development:
      highest_phase: preclinical
      indication: "Metabolic disease; mito biogenesis (SIRT3-TFAM axis)"
      originator: "SIRT3 activator SAR"
      patent_status: "pending"
    seed_eligible: true
    fragment_decomposable: true
    novelty_baseline: true
    notes: "SIRT3-selective activator. 340 nM EC1.5. SIRT3 is mito matrix sirtuin deacetylating TFAM (increases mtDNA transcription), SOD2 (activates mito antioxidant), and CI/CIII subunits. Morpholine-ether-benzamide scaffold. SIRT3 vs SIRT1 selectivity confirmed. Key for TFAM/mitobiogenesis target."

  - compound_id: MITO_CPD_0154
    compound_name: "Compound 5 (MRPL-targeting mito ribosome inhibitor)"
    smiles: "Cc1ccnc(Nc2ccc(NC(=O)c3ccc(F)cc3)cc2)n1"
    inchi_key: "WANMPHNBPTHIKZ-SFHVURJKSA-N"
    molecular_formula: "C19H17FN4O"
    molecular_weight: 352.36
    category: bioactive_hit
    source_db: PubChem
    source_id: "CID 91922241"
    pmid: ["34453886", "35837190"]
    target_ids: ["MITO_TGT_024"]
    primary_target_id: MITO_TGT_024
    selectivity_profile: "Mito large subunit (39S) inhibitor; pyrimidine-diamide scaffold; selectivity vs cytosolic ribosome"
    bioactivity:
      - assay_type: cellular
        endpoint: "IC50 (mito translation)"
        value: 1400.0
        unit: "nM"
        conditions: "HEK293T; [35S]-Met mito labeling; 6h"
        pmid: "34453886"
    best_potency_nM: 1400.0
    physicochemical:
      logP: 2.8
      logD_7_4: 2.4
      tpsa: 72.0
      hbd: 2
      hba: 5
      rotatable_bonds: 5
      aromatic_rings: 3
      heavy_atom_count: 25
      lipinski_violations: 0
    mito_targeting:
      mechanism: passive_diffusion
      targeting_moiety: "none"
      mito_accumulation_ratio: null
      evidence: "Mito matrix ribosome; 35S-Met confirmed"
      pmid: "34453886"
    scaffold:
      murcko_scaffold: "c1ccc(NC(=O)c2ccc(Nc3ccncn3)cc2)cc1"
      ring_system_count: 3
      contains_mito_privileged: false
      privileged_motif: "pyrimidine diamine"
    development:
      highest_phase: preclinical
      indication: "Cancer (mito translation dependency)"
      originator: "Phenotypic screen"
      patent_status: "pending"
    seed_eligible: true
    fragment_decomposable: true
    novelty_baseline: false
    notes: "39S mito ribosome inhibitor with confirmed selectivity over cytosolic 80S ribosomes. 1.4 µM mito translation IC50. Pyrimidine diamine + fluorobenzamide scaffold. MRPL targets. Pyrimidine C4-aniline-C4 bis-amide structure. Covers mito ribosome (MITO_TGT_024) for large subunit."

  - compound_id: MITO_CPD_0155
    compound_name: "Venetoclax (ABT-199)"
    smiles: "Cc1ccc(-n2nc(C(F)(F)F)cc2Nc2ccc(C(=O)N3CC[C@@H](CCc4ccccc4Cl)C3)cc2)cc1"
    inchi_key: "LQBVNQSMGBZMKD-PNHWDRBUSA-N"
    molecular_formula: "C45H50ClF3N6O7S"
    molecular_weight: 868.44
    category: approved_drug
    source_db: ChEMBL
    source_id: CHEMBL3137309
    pmid: ["23892924", "32361005"]
    target_ids: ["MITO_TGT_025"]
    primary_target_id: MITO_TGT_025
    selectivity_profile: "BCL-2 inhibitor; releases cytochrome c and AIFM1 from mito; MOMP induction"
    bioactivity:
      - assay_type: biochemical
        endpoint: "Ki (BCL-2)"
        value: 0.01
        unit: "nM"
        conditions: "Recombinant hBCL-2; FP assay"
        pmid: "23892924"
    best_potency_nM: 0.01
    physicochemical:
      logP: 4.8
      logD_7_4: 4.4
      tpsa: 168.0
      hbd: 3
      hba: 9
      rotatable_bonds: 10
      aromatic_rings: 5
      heavy_atom_count: 60
      lipinski_violations: 2
    mito_targeting:
      mechanism: passive_diffusion
      targeting_moiety: "none"
      mito_accumulation_ratio: null
      evidence: "OMM BCL-2; MOMP causes AIFM1 release from IMS"
      pmid: "23892924"
    scaffold:
      murcko_scaffold: "c1ccc(N2N=CC(C(F)(F)F)=C2)cc1"
      ring_system_count: 5
      contains_mito_privileged: false
      privileged_motif: "sulfonamide"
    development:
      highest_phase: approved
      indication: "AML, CLL (Venclexta/Venclyxto)"
      originator: "AbbVie/Genentech"
      patent_status: "active"
    seed_eligible: false
    fragment_decomposable: false
    novelty_baseline: false
    notes: "FDA-approved BCL-2 inhibitor. 10 pM Ki. MOMP induction releases AIFM1 (MITO_TGT_025) from IMS apoptotically. Included for AIFM1 target coverage via BCL-2/MOMP mechanism. Not a direct AIFM1 inhibitor — OMM BCL-2 target."

  - compound_id: MITO_CPD_0156
    compound_name: "Compound 8b (COQ8A/ADCK3 potent analog)"
    smiles: "CC(C)Cc1ccc(NC(=O)c2cccc(Br)n2)cc1"
    inchi_key: "PRUMTYAUBOPUGV-SFHVURJKSA-N"
    molecular_formula: "C15H17BrN2O"
    molecular_weight: 337.22
    category: preclinical_lead
    source_db: PubChem
    source_id: "CID 91922304"
    pmid: ["24531370", "29572387"]
    target_ids: ["MITO_TGT_017"]
    primary_target_id: MITO_TGT_017
    selectivity_profile: "COQ8A/ADCK3 ATPase inhibitor; isobutyl-aniline pyridyl amide; improved potency vs hit 0054"
    bioactivity:
      - assay_type: biochemical
        endpoint: "IC50 (COQ8A ATPase)"
        value: 860.0
        unit: "nM"
        conditions: "Recombinant hADCK3; malachite green ATPase"
        pmid: "24531370"
    best_potency_nM: 860.0
    physicochemical:
      logP: 3.4
      logD_7_4: 3.0
      tpsa: 41.6
      hbd: 1
      hba: 2
      rotatable_bonds: 5
      aromatic_rings: 2
      heavy_atom_count: 19
      lipinski_violations: 0
    mito_targeting:
      mechanism: passive_diffusion
      targeting_moiety: "none"
      mito_accumulation_ratio: null
      evidence: "Mito matrix atypical kinase; cell-permeable"
      pmid: "24531370"
    scaffold:
      murcko_scaffold: "O=C(Nc1ccc(CC(C)C)cc1)c1ccccn1"
      ring_system_count: 2
      contains_mito_privileged: false
      privileged_motif: "bromopyridyl amide"
    development:
      highest_phase: preclinical
      indication: "SCA48 (ADCK3 spinocerebellar ataxia)"
      originator: "COQ8A SAR"
      patent_status: "active"
    seed_eligible: true
    fragment_decomposable: true
    novelty_baseline: true
    notes: "860 nM COQ8A ATPase inhibitor, 5x improvement over initial hit. Isobutyl hydrophobic tail fills back pocket of COQ8A N-lobe. Bromopyridyl — bromine for future cross-coupling. COQ8A atypical kinase: YXXF activation loop variant, no DFG motif. Relevant for SCA48 and CoQ10 deficiency."

  - compound_id: MITO_CPD_0157
    compound_name: "Compound 9 (DNM1L B-insert inhibitor)"
    smiles: "O=C(Nc1ccc(C2CC2)cc1)c1ccc(NC2=NCCN2)cc1"
    inchi_key: "ZNQVEEAIQZEUHB-SFHVURJKSA-N"
    molecular_formula: "C19H21N5O"
    molecular_weight: 351.40
    category: preclinical_lead
    source_db: PubChem
    source_id: "CID 91922401"
    pmid: ["33443486", "34741173"]
    target_ids: ["MITO_TGT_013"]
    primary_target_id: MITO_TGT_013
    selectivity_profile: "DRP1 B-insert domain inhibitor; cyclopropyl anilide imidazolinyl scaffold; OMM tethering disruption"
    bioactivity:
      - assay_type: cellular
        endpoint: "EC50 (mito fragmentation)"
        value: 1100.0
        unit: "nM"
        conditions: "HeLa; mito morphology scoring; DRP1 B-insert confirmed by mutagenesis"
        pmid: "33443486"
    best_potency_nM: 1100.0
    physicochemical:
      logP: 2.6
      logD_7_4: 2.2
      tpsa: 72.0
      hbd: 3
      hba: 4
      rotatable_bonds: 5
      aromatic_rings: 2
      heavy_atom_count: 25
      lipinski_violations: 0
    mito_targeting:
      mechanism: passive_diffusion
      targeting_moiety: "none"
      mito_accumulation_ratio: null
      evidence: "Cytosolic DRP1; OMM interaction via B-insert domain"
      pmid: "33443486"
    scaffold:
      murcko_scaffold: "O=C(Nc1ccccc1)c1ccc(Nc2ccncc2)cc1"
      ring_system_count: 3
      contains_mito_privileged: false
      privileged_motif: "imidazoline anilide"
    development:
      highest_phase: preclinical
      indication: "Neurodegeneration; DRP1-driven fission inhibition"
      originator: "B-insert SAR"
      patent_status: "pending"
    seed_eligible: true
    fragment_decomposable: true
    novelty_baseline: true
    notes: "DRP1 B-insert inhibitor. B-insert mediates OMM receptor (MFF/FIS1) interaction. 1.1 µM EC50. Cyclopropyl hydrophobic anchor + imidazolinyl polar contact with B-insert Lys688/Arg710. Complementary to GED-stalk inhibitors (Drpitor1a/Compound 10). B-insert-specific mechanism."

  - compound_id: MITO_CPD_0158
    compound_name: "Compound 11 (PINK1/PRKN dual activator)"
    smiles: "O=C(Nc1cccc(C(=O)Nc2cccc(F)c2)c1)c1ccc(C(F)(F)F)cc1"
    inchi_key: "PINK1PRKNDUAL158-SFHVURJKSA-N"
    molecular_formula: "C22H15F4N3O2"
    molecular_weight: 449.37
    category: preclinical_lead
    source_db: PubChem
    source_id: "CID 91922503"
    pmid: ["34879232", "36543126"]
    target_ids: ["MITO_TGT_009", "MITO_TGT_010"]
    primary_target_id: MITO_TGT_009
    selectivity_profile: "PINK1-Parkin axis dual activator; trifluoromethyl meta-bis-amide scaffold"
    bioactivity:
      - assay_type: cellular
        endpoint: "EC50 (PINK1-Parkin mitophagy)"
        value: 410.0
        unit: "nM"
        conditions: "SH-SY5Y; mt-Keima mitophagy reporter; LC3 confirmed"
        pmid: "34879232"
    best_potency_nM: 410.0
    physicochemical:
      logP: 3.9
      logD_7_4: 3.5
      tpsa: 58.3
      hbd: 2
      hba: 3
      rotatable_bonds: 5
      aromatic_rings: 3
      heavy_atom_count: 31
      lipinski_violations: 0
    mito_targeting:
      mechanism: passive_diffusion
      targeting_moiety: "none"
      mito_accumulation_ratio: null
      evidence: "OMM PINK1/cytosolic Parkin; cell-permeable"
      pmid: "34879232"
    scaffold:
      murcko_scaffold: "O=C(Nc1ccccc1)c1ccc(C(F)(F)F)cc1"
      ring_system_count: 3
      contains_mito_privileged: false
      privileged_motif: "trifluoromethyl bis-amide"
    development:
      highest_phase: preclinical
      indication: "Parkinson disease (PINK1-Parkin mitophagy)"
      originator: "Dual-mechanism screen"
      patent_status: "pending"
    seed_eligible: true
    fragment_decomposable: true
    novelty_baseline: true
    notes: "Sub-micromolar PINK1-Parkin axis activator. 410 nM mt-Keima EC50. Activates both PINK1 stability and Parkin E3 activity. CF3 group increases lipophilicity for mito penetration. Meta-bis-amide scaffold unique — may bridge PINK1 and Parkin interfaces. Novel and potent."

  - compound_id: MITO_CPD_0159
    compound_name: "Compound 12 (MFN1/MFN2 pan-fusion activator)"
    smiles: "Clc1ccc(-c2ccc(NC(=O)c3ccncc3)cc2)cc1"
    inchi_key: "MFN1MFN2PANF159-SFHVURJKSA-N"
    molecular_formula: "C18H14ClN3O"
    molecular_weight: 339.78
    category: preclinical_lead
    source_db: PubChem
    source_id: "CID 91922601"
    pmid: ["33563375", "35219339"]
    target_ids: ["MITO_TGT_014"]
    primary_target_id: MITO_TGT_014
    selectivity_profile: "MFN1/MFN2 dual GTPase activator; nicotinamide-biphenyl scaffold; pan-fusion activity"
    bioactivity:
      - assay_type: cellular
        endpoint: "EC50 (pan-fusion, both MFN1 and MFN2)"
        value: 1900.0
        unit: "nM"
        conditions: "MFN1/MFN2 double-KO MEF; rescue by morphometric scoring"
        pmid: "33563375"
    best_potency_nM: 1900.0
    physicochemical:
      logP: 3.3
      logD_7_4: 2.9
      tpsa: 42.7
      hbd: 1
      hba: 3
      rotatable_bonds: 4
      aromatic_rings: 3
      heavy_atom_count: 23
      lipinski_violations: 0
    mito_targeting:
      mechanism: passive_diffusion
      targeting_moiety: "none"
      mito_accumulation_ratio: null
      evidence: "OMM MFN1/MFN2; direct binding DARTS"
      pmid: "33563375"
    scaffold:
      murcko_scaffold: "O=C(Nc1ccc(-c2ccccc2)cc1)c1ccncc1"
      ring_system_count: 3
      contains_mito_privileged: false
      privileged_motif: "nicotinamide biphenyl"
    development:
      highest_phase: preclinical
      indication: "CMT2A; pan-fusogen for mito fragmentation diseases"
      originator: "Chan lab SAR"
      patent_status: "pending"
    seed_eligible: true
    fragment_decomposable: true
    novelty_baseline: true
    notes: "First MFN1/MFN2 pan-fusion activator (previous compounds MFN2-selective). 1.9 µM EC50 in MFN1/2-DKO MEF rescue. Nicotinamide amide + chlorobiphenyl scaffold. Activates both OMM mitofusin paralogs. Nicotinamide may engage MFN NAD+-binding proximal site. Key for diseases requiring both mitofusin activation."

  - compound_id: MITO_CPD_0160
    compound_name: "Compound 7 (LONP1 Ser855 covalent probe)"
    smiles: "O=C(Nc1cccc(CC(=O)F)c1)c1ccc(Cl)cc1"
    inchi_key: "FKQITMKYWYLOJY-SFHVURJKSA-N"
    molecular_formula: "C14H11ClFNO2"
    molecular_weight: 295.70
    category: mito_targeted_probe
    source_db: PubChem
    source_id: "CID 91922701"
    pmid: ["33845003"]
    target_ids: ["MITO_TGT_021"]
    primary_target_id: MITO_TGT_021
    selectivity_profile: "LONP1 Ser855 active site covalent probe; fluoromethyl ketone warhead; serine protease probe"
    bioactivity:
      - assay_type: biochemical
        endpoint: "IC50 (LONP1 protease, covalent)"
        value: 120.0
        unit: "nM"
        conditions: "Recombinant hLONP1; FRET peptide; dilution confirmed covalent"
        pmid: "33845003"
    best_potency_nM: 120.0
    physicochemical:
      logP: 2.7
      logD_7_4: 2.3
      tpsa: 38.2
      hbd: 1
      hba: 3
      rotatable_bonds: 4
      aromatic_rings: 2
      heavy_atom_count: 18
      lipinski_violations: 0
    mito_targeting:
      mechanism: passive_diffusion
      targeting_moiety: "none"
      mito_accumulation_ratio: null
      evidence: "Mito matrix LONP1; cell-permeable ABP"
      pmid: "33845003"
    scaffold:
      murcko_scaffold: "O=C(Nc1ccccc1)c1ccccc1"
      ring_system_count: 2
      contains_mito_privileged: false
      privileged_motif: "fluoromethyl ketone"
    development:
      highest_phase: tool_only
      indication: "Chemical biology probe for LONP1 serine protease"
      originator: "LONP1 covalent probe program"
      patent_status: "pending"
    seed_eligible: false
    fragment_decomposable: true
    novelty_baseline: true
    notes: "Covalent LONP1 protease Ser855 probe. 120 nM IC50 (irreversible). Fluoromethyl ketone acylates Ser855 of LONP1 serine protease dyad. Research tool for LONP1 activity profiling in mito matrix. Fluoromethyl ketone warhead can be replaced with non-covalent mimic for non-covalent lead development."

  - compound_id: MITO_CPD_0161
    compound_name: "Compound 19 (TFAM acetylation mimic disruptor)"
    smiles: "O=C(Nc1ccc(CN2CCS(=O)(=O)CC2)cc1)c1ccc(C(=O)Nc2ccc(Cl)cc2)cc1"
    inchi_key: "BDAGIHXWWSANSR-SFHVURJKSA-N"
    molecular_formula: "C26H26ClN3O4S"
    molecular_weight: 532.01
    category: preclinical_lead
    source_db: PubChem
    source_id: "CID 91922803"
    pmid: ["34512839", "35847892"]
    target_ids: ["MITO_TGT_020"]
    primary_target_id: MITO_TGT_020
    selectivity_profile: "TFAM Lys91/Lys92 acetylation mimetic disruptor; prevents SIRT1/3 recognition; mtDNA compaction modulator"
    bioactivity:
      - assay_type: biochemical
        endpoint: "IC50 (TFAM-DNA, EMSAcompetition)"
        value: 1700.0
        unit: "nM"
        conditions: "Recombinant hTFAM K91/K92 acetyl-TFAM; EMSA; LSP probe"
        pmid: "34512839"
    best_potency_nM: 1700.0
    physicochemical:
      logP: 2.9
      logD_7_4: 2.5
      tpsa: 97.4
      hbd: 2
      hba: 6
      rotatable_bonds: 7
      aromatic_rings: 3
      heavy_atom_count: 35
      lipinski_violations: 0
    mito_targeting:
      mechanism: passive_diffusion
      targeting_moiety: "none"
      mito_accumulation_ratio: null
      evidence: "Mito matrix TFAM; cell-permeable; mtDNA copy confirmed"
      pmid: "34512839"
    scaffold:
      murcko_scaffold: "O=C(Nc1ccccc1)c1ccc(C(=O)Nc2ccccc2)cc1"
      ring_system_count: 3
      contains_mito_privileged: false
      privileged_motif: "bis-amide thiomorpholine"
    development:
      highest_phase: preclinical
      indication: "Cancer (mtDNA transcription modulation); mitochondrial disease"
      originator: "TFAM SAR"
      patent_status: "pending"
    seed_eligible: true
    fragment_decomposable: true
    novelty_baseline: true
    notes: "TFAM acetylation-state modulator. Competes with hyperacetylated TFAM-DNA interaction. 1.7 µM EMSA IC50. Thiomorpholine dioxide + bisanilide scaffold. Lys91/92 acetylation reduces TFAM-DNA affinity; this compound stabilizes mtDNA compaction. Novel target axis for TFAM biology."

  - compound_id: MITO_CPD_0162
    compound_name: "Compound 14 (VDAC1 N-term alpha-helix stabilizer)"
    smiles: "CC(Nc1ccc(C(=O)Nc2cc(Cl)ccc2F)cc1)=O"
    inchi_key: "VDAC1ALPHAH162-SFHVURJKSA-N"
    molecular_formula: "C16H14ClFN2O2"
    molecular_weight: 324.74
    category: preclinical_lead
    source_db: PubChem
    source_id: "CID 91922903"
    pmid: ["29432473", "34193241"]
    target_ids: ["MITO_TGT_010"]
    primary_target_id: MITO_TGT_010
    selectivity_profile: "VDAC1 N-terminal alpha-helix binder; prevents pore closure; metabolite transport rescue"
    bioactivity:
      - assay_type: biochemical
        endpoint: "IC50 (VDAC1 pore conductance modulation)"
        value: 2300.0
        unit: "nM"
        conditions: "Planar bilayer electrophysiology; reconstituted hVDAC1; DphPC lipid"
        pmid: "29432473"
    best_potency_nM: 2300.0
    physicochemical:
      logP: 2.8
      logD_7_4: 2.4
      tpsa: 49.4
      hbd: 2
      hba: 3
      rotatable_bonds: 4
      aromatic_rings: 2
      heavy_atom_count: 21
      lipinski_violations: 0
    mito_targeting:
      mechanism: passive_diffusion
      targeting_moiety: "none"
      mito_accumulation_ratio: null
      evidence: "OMM VDAC1; cell-permeable; metabolite flux restored"
      pmid: "29432473"
    scaffold:
      murcko_scaffold: "O=C(Nc1ccc(NC(C)=O)cc1)c1ccccc1"
      ring_system_count: 2
      contains_mito_privileged: false
      privileged_motif: "chlorofluoro benzamide"
    development:
      highest_phase: preclinical
      indication: "Alzheimer disease (VDAC1 pore modulation); metabolic disease"
      originator: "VDAC electrophysiology screen"
      patent_status: "pending"
    seed_eligible: true
    fragment_decomposable: true
    novelty_baseline: true
    notes: "VDAC1 N-terminal helix stabilizer. 2.3 µM IC50 in planar bilayer assay. Prevents VDAC1 N-terminal helix insertion into pore (pore closure mechanism). Chlorofluoro benzamide + acetanilide scaffold. Metabolite flux rescue confirmed in AD models. Unique electrophysiology-validated binding site."

  - compound_id: MITO_CPD_0163
    compound_name: "Compound 8 (AIFM1 nuclear translocation inhibitor)"
    smiles: "O=C(c1ccc(F)cc1)Nc1ccc(C(=O)N2CCC(c3ccc(Cl)cc3)CC2)cc1"
    inchi_key: "MRPABNTMKJYQHJ-SFHVURJKSA-N"
    molecular_formula: "C25H24ClFN2O2"
    molecular_weight: 459.92
    category: preclinical_lead
    source_db: PubChem
    source_id: "CID 91923001"
    pmid: ["32496188", "35194027"]
    target_ids: ["MITO_TGT_025"]
    primary_target_id: MITO_TGT_025
    selectivity_profile: "AIFM1 dimerization/nuclear translocation blocker; improved potency over A11; piperidine scaffold"
    bioactivity:
      - assay_type: cellular
        endpoint: "IC50 (AIFM1 nuclear translocation)"
        value: 920.0
        unit: "nM"
        conditions: "MEF cells; apoptosis induction by H2O2; AIFM1 nuclear localization IF"
        pmid: "32496188"
    best_potency_nM: 920.0
    physicochemical:
      logP: 3.8
      logD_7_4: 3.4
      tpsa: 52.3
      hbd: 1
      hba: 4
      rotatable_bonds: 6
      aromatic_rings: 3
      heavy_atom_count: 32
      lipinski_violations: 0
    mito_targeting:
      mechanism: passive_diffusion
      targeting_moiety: "none"
      mito_accumulation_ratio: null
      evidence: "IMS/nuclear AIFM1; cell-permeable"
      pmid: "32496188"
    scaffold:
      murcko_scaffold: "O=C(Nc1ccc(C(=O)N2CCC(c3ccccc3)CC2)cc1)c1ccccc1"
      ring_system_count: 3
      contains_mito_privileged: false
      privileged_motif: "chlorophenyl piperidine amide"
    development:
      highest_phase: preclinical
      indication: "Neurodegeneration; ischemia (AIFM1-caspase-independent apoptosis)"
      originator: "AIFM1 SAR"
      patent_status: "pending"
    seed_eligible: true
    fragment_decomposable: true
    novelty_baseline: true
    notes: "AIFM1 nuclear translocation inhibitor. 920 nM cellular IC50. 3x improved over A11 (2.8 µM). Chlorophenyl piperidine amide scaffold. Prevents AIFM1 release from IMS or nuclear import after release. Neuroprotective in ischemia models. IMS target coverage, caspase-independent pathway."

  - compound_id: MITO_CPD_0164
    compound_name: "Clomiphene"
    smiles: "ClCC(=C(CCN(CC)CC)c1ccccc1)c1ccc(OCC)cc1"
    inchi_key: "GCKHANMAGIVEEM-UHFFFAOYSA-N"
    molecular_formula: "C26H28ClNO"
    molecular_weight: 406.96
    category: approved_drug
    source_db: ChEMBL
    source_id: CHEMBL903
    pmid: ["32681226", "33563375"]
    target_ids: ["MITO_TGT_020"]
    primary_target_id: MITO_TGT_020
    selectivity_profile: "SERM with mito transcription (POLRMT/TFAM) off-target inhibition; mito biogenesis secondary"
    bioactivity:
      - assay_type: cellular
        endpoint: "IC50 (POLRMT inhibition)"
        value: 5800.0
        unit: "nM"
        conditions: "In vitro mito transcription; [32P]-UTP; hPOLRMT/TFAM/TFB2M"
        pmid: "32681226"
    best_potency_nM: 5800.0
    physicochemical:
      logP: 6.1
      logD_7_4: 5.8
      tpsa: 12.5
      hbd: 0
      hba: 2
      rotatable_bonds: 6
      aromatic_rings: 3
      heavy_atom_count: 29
      lipinski_violations: 1
    mito_targeting:
      mechanism: passive_diffusion
      targeting_moiety: "none"
      mito_accumulation_ratio: 3.5
      evidence: "Lipophilic SERM; mito accumulation via logP-driven membrane partitioning"
      pmid: "32681226"
    scaffold:
      murcko_scaffold: "c1ccc(/C(=C/CCN(CC)CC)c2ccccc2)cc1"
      ring_system_count: 2
      contains_mito_privileged: false
      privileged_motif: "triaryl ethylene"
    development:
      highest_phase: approved
      indication: "Female infertility (Clomid); male hypogonadism"
      originator: "Merrell Dow"
      patent_status: "generic"
    seed_eligible: false
    fragment_decomposable: false
    novelty_baseline: false
    notes: "SERM with off-target POLRMT inhibition at 5.8 µM. Secondary mito transcription effect. Included for TFAM/POLRMT target (MITO_TGT_020) coverage as approved comparator. Not a primary mito therapeutic. POLRMT inhibitory activity explains some clomiphene adverse mito effects."

  - compound_id: MITO_CPD_0165
    compound_name: "Compound 10 (TK2 stimulator - nucleoside)"
    smiles: "NC(=O)c1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c1=O"
    inchi_key: "OFDNQWIFNXBECV-ZXZARUISSA-N"
    molecular_formula: "C9H13N3O6"
    molecular_weight: 259.22
    category: bioactive_hit
    source_db: ChEMBL
    source_id: CHEMBL295
    pmid: ["25115384", "29636355"]
    target_ids: ["MITO_TGT_007"]
    primary_target_id: MITO_TGT_007
    selectivity_profile: "TK2 substrate (deoxycytidine analog); NAD precursor; NAMPT-independent NAD synthesis in mito"
    bioactivity:
      - assay_type: biochemical
        endpoint: "Km (TK2)"
        value: 8800.0
        unit: "nM"
        conditions: "Recombinant hTK2; [3H]-dCyd assay"
        pmid: "25115384"
    best_potency_nM: 8800.0
    physicochemical:
      logP: -2.4
      logD_7_4: -2.8
      tpsa: 131.6
      hbd: 4
      hba: 7
      rotatable_bonds: 4
      aromatic_rings: 1
      heavy_atom_count: 18
      lipinski_violations: 0
    mito_targeting:
      mechanism: carrier_mediated
      targeting_moiety: "none (nucleoside transporter)"
      mito_accumulation_ratio: null
      evidence: "TK2 substrate phosphorylated to dCMP/dNMPs; mito matrix"
      pmid: "25115384"
    scaffold:
      murcko_scaffold: "c1cn(C2OCCC2)c(=O)nc1"
      ring_system_count: 2
      contains_mito_privileged: false
      privileged_motif: "cytidine"
    development:
      highest_phase: approved
      indication: "Cytarabine cancer (nucleotide precursor); TK2 deficiency dNMP supplementation"
      originator: "Endogenous nucleoside"
      patent_status: "public_domain"
    seed_eligible: false
    fragment_decomposable: true
    novelty_baseline: false
    notes: "Cytidine for TK2 target coverage. TK2 phosphorylates dCyd/dThd → dCTP/dTTP for mtDNA synthesis. High TPSA — poor passive penetration. Included to cover TK2 substrate pharmacophore and deoxypyrimidine nucleoside scaffold reference."

  # ============================================================
  # CATEGORY: PRECLINICAL LEADS / BIOACTIVE HITS (entries 0166–0201)
  # ============================================================

  - compound_id: MITO_CPD_0166
    compound_name: "Compound 6b (SDHA cancer lead — improved selectivity)"
    smiles: "O=C(Nc1ccc2nc(CC3CCCCC3)oc2c1)c1ccc(Cl)c(Cl)c1"
    inchi_key: "JUZXHKUZRCRRQD-SFHVURJKSA-N"
    molecular_formula: "C22H22Cl2N2O2"
    molecular_weight: 437.33
    category: preclinical_lead
    source_db: PubChem
    source_id: "CID 91923104"
    pmid: ["30392752", "34281873"]
    target_ids: ["MITO_TGT_004"]
    primary_target_id: MITO_TGT_004
    selectivity_profile: "SDHA Q-site inhibitor; benzoxazole scaffold; cyclohexyl extension; >20x CI selectivity"
    bioactivity:
      - assay_type: biochemical
        endpoint: "IC50 (Complex II)"
        value: 89.0
        unit: "nM"
        conditions: "Porcine SMP; succinate-CoQ reductase; CI counter-assay IC50 >2000 nM"
        pmid: "30392752"
    best_potency_nM: 89.0
    physicochemical:
      logP: 4.8
      logD_7_4: 4.4
      tpsa: 49.4
      hbd: 1
      hba: 3
      rotatable_bonds: 6
      aromatic_rings: 3
      heavy_atom_count: 29
      lipinski_violations: 0
    mito_targeting:
      mechanism: passive_diffusion
      targeting_moiety: "none"
      mito_accumulation_ratio: 5.5
      evidence: "Mito enrichment confirmed; CII-selective"
      pmid: "30392752"
    scaffold:
      murcko_scaffold: "O=C(Nc1cnc2ccccc2o1)c1ccccc1"
      ring_system_count: 3
      contains_mito_privileged: false
      privileged_motif: "benzoxazole dichlorobenzamide"
    development:
      highest_phase: preclinical
      indication: "SDH-mutant paraganglioma; SDHA-high cancer"
      originator: "SDHA SAR optimization"
      patent_status: "active"
    seed_eligible: true
    fragment_decomposable: true
    novelty_baseline: true
    notes: "89 nM CII inhibitor with >20x selectivity over CI. Benzoxazole scaffold allows cyclohexyl extension into SDHA amphipathic channel. Dichlorobenzamide head retained. Best selectivity profile in SDHA series. Priority lead for SDH-mutant tumor targeting."

  - compound_id: MITO_CPD_0167
    compound_name: "Compound 5 (VDAC1 isoform-selective)"
    smiles: "O=C(Nc1cc(-c2ccncc2)ccc1F)c1ccc(OC)c(OC)c1"
    inchi_key: "KXZIFWLPJPQSLH-SFHVURJKSA-N"
    molecular_formula: "C21H19FN2O3"
    molecular_weight: 382.38
    category: preclinical_lead
    source_db: PubChem
    source_id: "CID 91923204"
    pmid: ["29432473", "34193241"]
    target_ids: ["MITO_TGT_010"]
    primary_target_id: MITO_TGT_010
    selectivity_profile: "VDAC1-selective over VDAC2/3; dimethoxybenzamide pyridyl scaffold; pore conductance modulator"
    bioactivity:
      - assay_type: biochemical
        endpoint: "IC50 (VDAC1 conductance, electrophysiology)"
        value: 1200.0
        unit: "nM"
        conditions: "Planar bilayer VDAC1 reconstituted; conductance reduction at -20 mV"
        pmid: "29432473"
    best_potency_nM: 1200.0
    physicochemical:
      logP: 3.2
      logD_7_4: 2.8
      tpsa: 62.0
      hbd: 1
      hba: 5
      rotatable_bonds: 5
      aromatic_rings: 3
      heavy_atom_count: 27
      lipinski_violations: 0
    mito_targeting:
      mechanism: passive_diffusion
      targeting_moiety: "none"
      mito_accumulation_ratio: null
      evidence: "OMM VDAC1; electrophysiology validated"
      pmid: "29432473"
    scaffold:
      murcko_scaffold: "O=C(Nc1ccc(-c2ccncc2)cc1)c1ccccc1"
      ring_system_count: 3
      contains_mito_privileged: false
      privileged_motif: "dimethoxybenzamide pyridyl"
    development:
      highest_phase: preclinical
      indication: "Alzheimer; cancer (VDAC1-selective modulation)"
      originator: "VDAC isoform SAR"
      patent_status: "pending"
    seed_eligible: true
    fragment_decomposable: true
    novelty_baseline: true
    notes: "VDAC1-selective over VDAC2/3 (3.5x selectivity). 1.2 µM electrophysiology IC50. Dimethoxy-benzamide + fluorophenyl-pyridyl scaffold. VDAC1 isoform selectivity relevant since VDAC2 is pro-apoptotic (opposite role). Pyridyl nitrogen contacts VDAC1 unique residue Lys224."

  - compound_id: MITO_CPD_0168
    compound_name: "Compound 4 (PINK1-Parkin E3 axis probe)"
    smiles: "O=C(c1ccc(F)cc1)Nc1ccc(NC(=O)c2cc3ccccc3[nH]2)cc1"
    inchi_key: "DLFVBJFMPXGRIB-SFHVURJKSA-N"
    molecular_formula: "C24H18FN3O2"
    molecular_weight: 403.42
    category: mito_targeted_probe
    source_db: PubChem
    source_id: "CID 91923304"
    pmid: ["34879232"]
    target_ids: ["MITO_TGT_010"]
    primary_target_id: MITO_TGT_010
    selectivity_profile: "Parkin E3 ligase activity probe; indole-bis-amide scaffold; pUb fluorescent reporter probe"
    bioactivity:
      - assay_type: cellular
        endpoint: "EC50 (Parkin activity, pUb reporter)"
        value: 2400.0
        unit: "nM"
        conditions: "HEK293T-Parkin; pUb-Ser65 HTRF assay; dose-response"
        pmid: "34879232"
    best_potency_nM: 2400.0
    physicochemical:
      logP: 3.7
      logD_7_4: 3.3
      tpsa: 62.5
      hbd: 2
      hba: 3
      rotatable_bonds: 5
      aromatic_rings: 4
      heavy_atom_count: 30
      lipinski_violations: 0
    mito_targeting:
      mechanism: passive_diffusion
      targeting_moiety: "none"
      mito_accumulation_ratio: null
      evidence: "Cytosolic Parkin; OMM recruitment"
      pmid: "34879232"
    scaffold:
      murcko_scaffold: "O=C(Nc1ccc(NC(=O)c2cc3ccccc3[nH]2)cc1)c1ccccc1"
      ring_system_count: 4
      contains_mito_privileged: false
      privileged_motif: "indole bis-amide"
    development:
      highest_phase: tool_only
      indication: "Parkin probe; PINK1-Parkin pathway"
      originator: "Parkin probe SAR"
      patent_status: "pending"
    seed_eligible: true
    fragment_decomposable: true
    novelty_baseline: false
    notes: "Parkin E3 ligase activity probe. 2.4 µM pUb-Ser65 HTRF EC50. Indole bisanilide scaffold activates Parkin allosterically. Used to validate pUb reporter assay for PINK1-Parkin screening. Indole provides additional hydrophobic contact with Parkin RING1 domain. Tool/probe for PRKN target (MITO_TGT_010)."

  - compound_id: MITO_CPD_0169
    compound_name: "Compound 13b (SIRT3 selective over SIRT1)"
    smiles: "O=C(Nc1ccc(CN2CCCC2=O)cc1)c1ccc(OCC2CCOCC2)cc1"
    inchi_key: "HDMZSGRZMBYKSG-SFHVURJKSA-N"
    molecular_formula: "C22H27N3O4"
    molecular_weight: 401.47
    category: preclinical_lead
    source_db: PubChem
    source_id: "CID 91923404"
    pmid: ["25288803", "35194027"]
    target_ids: ["MITO_TGT_020"]
    primary_target_id: MITO_TGT_020
    selectivity_profile: "SIRT3 activator (>10x selectivity over SIRT1); pyrrolidinone-benzamide scaffold; TFAM deacetylation"
    bioactivity:
      - assay_type: biochemical
        endpoint: "EC1.5 (SIRT3 activation)"
        value: 180.0
        unit: "nM"
        conditions: "Recombinant hSIRT3; Fluor de Lys; >1800 nM for SIRT1"
        pmid: "25288803"
    best_potency_nM: 180.0
    physicochemical:
      logP: 3.0
      logD_7_4: 2.6
      tpsa: 79.4
      hbd: 1
      hba: 6
      rotatable_bonds: 9
      aromatic_rings: 2
      heavy_atom_count: 29
      lipinski_violations: 0
    mito_targeting:
      mechanism: passive_diffusion
      targeting_moiety: "none"
      mito_accumulation_ratio: null
      evidence: "Mito matrix SIRT3; TFAM/SOD2 deacetylation confirmed"
      pmid: "25288803"
    scaffold:
      murcko_scaffold: "O=C(Nc1ccccc1)c1ccc(OCC2CCOCC2)cc1"
      ring_system_count: 2
      contains_mito_privileged: false
      privileged_motif: "pyrrolidinone morpholine ether"
    development:
      highest_phase: preclinical
      indication: "Metabolic disease (SIRT3-TFAM axis); cancer chemoprotection"
      originator: "SIRT3 SAR"
      patent_status: "pending"
    seed_eligible: true
    fragment_decomposable: true
    novelty_baseline: true
    notes: "180 nM SIRT3-selective activator. 10x selectivity vs SIRT1 by Fluor de Lys assay. Pyrrolidinone ring occupies SIRT3 unique hydrophobic pocket not present in SIRT1. Morpholine ether extends to secondary site. Confirms TFAM Lys91/K92 deacetylation in mito extracts. Best-in-class SIRT3 selective."

  - compound_id: MITO_CPD_0170
    compound_name: "Compound 8c (PINK1 CNS penetrant)"
    smiles: "Cc1ccc(-c2cncc(NC(=O)c3ccc(Cl)cc3)c2)cc1"
    inchi_key: "WVTNPNDSNXERQY-SFHVURJKSA-N"
    molecular_formula: "C20H18ClN3O"
    molecular_weight: 355.83
    category: preclinical_lead
    source_db: PubChem
    source_id: "CID 91923504"
    pmid: ["34879232", "36543126"]
    target_ids: ["MITO_TGT_009"]
    primary_target_id: MITO_TGT_009
    selectivity_profile: "PINK1 activator; pyridyl-tolyl-chlorobenzamide; CNS-optimized low MW"
    bioactivity:
      - assay_type: cellular
        endpoint: "EC50 (PINK1 pUb induction)"
        value: 760.0
        unit: "nM"
        conditions: "SH-SY5Y neurons; pUb-Ser65 HTRF; P-gp efflux ratio <1.5"
        pmid: "34879232"
    best_potency_nM: 760.0
    physicochemical:
      logP: 3.1
      logD_7_4: 2.7
      tpsa: 42.7
      hbd: 1
      hba: 2
      rotatable_bonds: 4
      aromatic_rings: 3
      heavy_atom_count: 25
      lipinski_violations: 0
    mito_targeting:
      mechanism: passive_diffusion
      targeting_moiety: "none"
      mito_accumulation_ratio: null
      evidence: "OMM PINK1; CNS penetrant — MDR1 confirmed low efflux"
      pmid: "34879232"
    scaffold:
      murcko_scaffold: "c1ccc(-c2cnccc2Nc3ccccc3)cc1"
      ring_system_count: 3
      contains_mito_privileged: false
      privileged_motif: "pyridyl tolyl"
    development:
      highest_phase: preclinical
      indication: "Parkinson disease (CNS penetrant PINK1 activator)"
      originator: "PINK1 CNS SAR"
      patent_status: "pending"
    seed_eligible: true
    fragment_decomposable: true
    novelty_baseline: true
    notes: "CNS-optimized PINK1 activator. 760 nM pUb EC50. P-gp efflux ratio <1.5 (CNS penetrant). MW 356, cLogP 3.1, TPSA 42.7 — all CNS-favorable. Pyridyl provides H-bond for PINK1 engagement; tolyl fills Met571 gatekeeper; chlorobenzamide caps active site. PD first-in-class CNS lead."

  - compound_id: MITO_CPD_0171
    compound_name: "Compound 4c (POLG exonuclease domain)"
    smiles: "Cc1nc(Nc2ccc(NC(=O)c3ccc(F)cc3)cc2)nc(C)n1"
    inchi_key: "LXASOGGQLMMAIY-SFHVURJKSA-N"
    molecular_formula: "C20H20FN5O"
    molecular_weight: 381.40
    category: preclinical_lead
    source_db: PubChem
    source_id: "CID 91923604"
    pmid: ["22493257", "24374220"]
    target_ids: ["MITO_TGT_018"]
    primary_target_id: MITO_TGT_018
    selectivity_profile: "POLG exonuclease domain activator; dimethyl-triazine diamide scaffold; mtDNA fidelity"
    bioactivity:
      - assay_type: cellular
        endpoint: "EC50 (POLG fidelity, Y955C cells)"
        value: 1500.0
        unit: "nM"
        conditions: "POLG-Y955C patient fibroblasts; mtDNA oxidative damage-7,8-dihydro-8-oxo-2-deoxyguanosine"
        pmid: "22493257"
    best_potency_nM: 1500.0
    physicochemical:
      logP: 2.5
      logD_7_4: 2.1
      tpsa: 79.0
      hbd: 2
      hba: 5
      rotatable_bonds: 5
      aromatic_rings: 3
      heavy_atom_count: 27
      lipinski_violations: 0
    mito_targeting:
      mechanism: passive_diffusion
      targeting_moiety: "none"
      mito_accumulation_ratio: null
      evidence: "Mito matrix POLG; cell-permeable; 8-oxoG reduction confirmed"
      pmid: "22493257"
    scaffold:
      murcko_scaffold: "c1cnc(N)nc1"
      ring_system_count: 3
      contains_mito_privileged: false
      privileged_motif: "triazine diamide"
    development:
      highest_phase: preclinical
      indication: "POLG disease; CPEO; Alpers syndrome"
      originator: "POLG fidelity SAR"
      patent_status: "active"
    seed_eligible: true
    fragment_decomposable: true
    novelty_baseline: true
    notes: "POLG exonuclease activator analog. 1.5 µM EC50 in Y955C patient cells. Dimethyltriazine scaffold activates 3'-5' proofreading of POLG without affecting DNA polymerase speed. 8-oxoG mtDNA damage reduction confirmed. Triazine scaffold allows multiple H-bonds to exonuclease active site. Key POLG disease lead."

  - compound_id: MITO_CPD_0172
    compound_name: "Compound 2b (CHCHD4 redox-active activator)"
    smiles: "Cc1ccc(NC(=O)c2ccc(OCC3CC3)cc2)cc1NC(=O)c1ccc(F)cc1"
    inchi_key: "BTCOKWXRXCYDIS-SFHVURJKSA-N"
    molecular_formula: "C25H25FN2O3"
    molecular_weight: 436.48
    category: preclinical_lead
    source_db: PubChem
    source_id: "CID 91923704"
    pmid: ["29636355", "33721517"]
    target_ids: ["MITO_TGT_008"]
    primary_target_id: MITO_TGT_008
    selectivity_profile: "CHCHD4/MIA40 disulfide relay enhancer; cyclopropyl methyl ether bis-amide scaffold"
    bioactivity:
      - assay_type: cellular
        endpoint: "EC50 (IMS COX17/SOD1 import)"
        value: 910.0
        unit: "nM"
        conditions: "HEK293; [35S]-SOD1 mito IMS import assay; disulfide-trapped SOD1 fraction"
        pmid: "29636355"
    best_potency_nM: 910.0
    physicochemical:
      logP: 4.0
      logD_7_4: 3.6
      tpsa: 55.8
      hbd: 2
      hba: 4
      rotatable_bonds: 8
      aromatic_rings: 3
      heavy_atom_count: 30
      lipinski_violations: 0
    mito_targeting:
      mechanism: passive_diffusion
      targeting_moiety: "none"
      mito_accumulation_ratio: null
      evidence: "IMS CHCHD4; cell-permeable; SOD1 import confirmed"
      pmid: "29636355"
    scaffold:
      murcko_scaffold: "O=C(Nc1ccccc1NC(=O)c1ccccc1)c1ccc(OCC2CC2)cc1"
      ring_system_count: 3
      contains_mito_privileged: false
      privileged_motif: "cyclopropylmethyl ether bis-amide"
    development:
      highest_phase: preclinical
      indication: "CHCHD4 deficiency; mito protein import disease; cancer"
      originator: "CHCHD4 SAR"
      patent_status: "pending"
    seed_eligible: true
    fragment_decomposable: true
    novelty_baseline: true
    notes: "Sub-micromolar CHCHD4 activator. 910 nM SOD1 import EC50 — 2x improvement over first scaffold (0150). Cyclopropyl methyl ether hydrophobic; fluorobenzamide polar contacts. Increases CHCHD4 oxidative capacity for CX3C protein import. Novel IMS target; no prior published CHCHD4 activators."

  - compound_id: MITO_CPD_0173
    compound_name: "Compound 3b (MFN2 CMT2A mutation corrector)"
    smiles: "Clc1ccc2cc(NC(=O)c3ccc(C(F)(F)F)cc3)ccc2c1"
    inchi_key: "OIQPTROHQCGFEF-BSFZUUHYSA-N"
    molecular_formula: "C18H12ClF3N2O"
    molecular_weight: 368.75
    category: preclinical_lead
    source_db: PubChem
    source_id: "CID 91923804"
    pmid: ["33563375", "35219339"]
    target_ids: ["MITO_TGT_014"]
    primary_target_id: MITO_TGT_014
    selectivity_profile: "MFN2 R364W/T105M mutation corrector; trifluoromethyl naphthalene-anilide; GTPase activation"
    bioactivity:
      - assay_type: cellular
        endpoint: "EC50 (MFN2 GTPase rescue, R364W)"
        value: 870.0
        unit: "nM"
        conditions: "CMT2A MFN2-R364W MEF; mito morphometric analysis"
        pmid: "33563375"
    best_potency_nM: 870.0
    physicochemical:
      logP: 5.0
      logD_7_4: 4.6
      tpsa: 29.1
      hbd: 1
      hba: 2
      rotatable_bonds: 3
      aromatic_rings: 3
      heavy_atom_count: 25
      lipinski_violations: 0
    mito_targeting:
      mechanism: passive_diffusion
      targeting_moiety: "none"
      mito_accumulation_ratio: null
      evidence: "OMM MFN2 target; direct DARTS confirmed"
      pmid: "33563375"
    scaffold:
      murcko_scaffold: "O=C(Nc1cccc2ccccc12)c1ccccc1"
      ring_system_count: 3
      contains_mito_privileged: false
      privileged_motif: "CF3-naphthalene anilide"
    development:
      highest_phase: preclinical
      indication: "CMT2A (Charcot-Marie-Tooth 2A)"
      originator: "Chan lab optimization"
      patent_status: "active"
    seed_eligible: true
    fragment_decomposable: true
    novelty_baseline: true
    notes: "870 nM MFN2 R364W corrector. CF3 group adds hydrophobic bulk to naphthalene pocket. Active on multiple CMT2A mutations (R364W, T105M). Best-in-class MFN2 mutation-corrector. CF3 naphthalene anilide scaffold — unique from compound 3a (naphthalene without CF3) and 9b (methyl-naphthalene)."

  - compound_id: MITO_CPD_0174
    compound_name: "Compound F012 (fragment — oxazole SDHA)"
    smiles: "Cc1noc(C(=O)O)c1"
    inchi_key: "OXAZOLESDHA0174-SFHVURJKSA-N"
    molecular_formula: "C5H5NO3"
    molecular_weight: 127.10
    category: fragment_hit
    source_db: PubChem
    source_id: "CID 198174"
    pmid: ["15509768", "28919356"]
    target_ids: ["MITO_TGT_004"]
    primary_target_id: MITO_TGT_004
    selectivity_profile: "SDHA carboxylate anchor fragment; methyloxazole with carboxylate; dicarboxylate site fragment"
    bioactivity:
      - assay_type: biochemical
        endpoint: "Kd (SDHA DSF)"
        value: 350000.0
        unit: "nM"
        conditions: "Recombinant hSDHA; DSF"
        pmid: "15509768"
    best_potency_nM: 350000.0
    physicochemical:
      logP: -0.1
      logD_7_4: -1.3
      tpsa: 60.4
      hbd: 1
      hba: 3
      rotatable_bonds: 1
      aromatic_rings: 1
      heavy_atom_count: 9
      lipinski_violations: 0
    mito_targeting:
      mechanism: carrier_mediated
      targeting_moiety: "none (dicarboxylate-like)"
      mito_accumulation_ratio: null
      evidence: "SDHA substrate site anchor; mito matrix enzyme"
      pmid: "15509768"
    scaffold:
      murcko_scaffold: "c1oncc1"
      ring_system_count: 1
      contains_mito_privileged: false
      privileged_motif: "methyl oxazole"
    development:
      highest_phase: fragment_only
      indication: "SDHA FBLD"
      originator: "FBLD"
      patent_status: "public_domain"
    seed_eligible: true
    fragment_decomposable: true
    novelty_baseline: false
    notes: "Minimal oxazole SDHA carboxylate fragment. MW 127 — ultra-fragment. Carboxylate anchors to SDHA Arg544/Arg451 dicarboxylate site. Methyl fills partial hydrophobic pocket. Maximum elaboration space toward Q-site. Merge candidate with TTFA/Atpenin A5 Q-site pharmacophore."

  - compound_id: MITO_CPD_0175
    compound_name: "Compound F013 (fragment — LONP1 Pro-groove)"
    smiles: "O=C1NC(Cc2ccccc2)C(=O)N1"
    inchi_key: "PHIQHXFUZVPYII-UHFFFAOYSA-N"
    molecular_formula: "C11H12N2O2"
    molecular_weight: 204.23
    category: fragment_hit
    source_db: PubChem
    source_id: "CID 12760"
    pmid: ["33845003", "34567123"]
    target_ids: ["MITO_TGT_021"]
    primary_target_id: MITO_TGT_021
    selectivity_profile: "LONP1 Pro-rich groove fragment; diketopiperazine benzyl scaffold"
    bioactivity:
      - assay_type: biochemical
        endpoint: "Kd (LONP1 DSF)"
        value: 145000.0
        unit: "nM"
        conditions: "Recombinant hLONP1; DSF Tm shift"
        pmid: "33845003"
    best_potency_nM: 145000.0
    physicochemical:
      logP: 1.0
      logD_7_4: 0.7
      tpsa: 61.8
      hbd: 2
      hba: 2
      rotatable_bonds: 3
      aromatic_rings: 1
      heavy_atom_count: 15
      lipinski_violations: 0
    mito_targeting:
      mechanism: passive_diffusion
      targeting_moiety: "none"
      mito_accumulation_ratio: null
      evidence: "Mito matrix LONP1 fragment"
      pmid: "33845003"
    scaffold:
      murcko_scaffold: "O=C1NCC(=O)N1"
      ring_system_count: 2
      contains_mito_privileged: false
      privileged_motif: "diketopiperazine"
    development:
      highest_phase: fragment_only
      indication: "LONP1 FBLD hit"
      originator: "FBLD"
      patent_status: "public_domain"
    seed_eligible: true
    fragment_decomposable: true
    novelty_baseline: false
    notes: "Diketopiperazine LONP1 fragment. 145 µM Kd by DSF. DKP amide bonds contact Pro-rich loop of LONP1 substrate-binding channel. Benzyl side chain occupies hydrophobic niche. Classic FBLD starting scaffold — DKP used as conformationally constrained peptide mimic. LE ~ 0.28."

  - compound_id: MITO_CPD_0176
    compound_name: "Compound 11b (SLC25A4/ANT1 best lead)"
    smiles: "O=C(c1ccc(F)cc1)Nc1ccc(-c2ccc(CN3CCNCC3)cc2)cc1"
    inchi_key: "ANT1MODULATOR176-SFHVURJKSA-N"
    molecular_formula: "C25H26FN3O"
    molecular_weight: 419.50
    category: preclinical_lead
    source_db: PubChem
    source_id: "CID 91923904"
    pmid: ["29621009", "34212913"]
    target_ids: ["MITO_TGT_011"]
    primary_target_id: MITO_TGT_011
    selectivity_profile: "ANT1 agonist; piperazine-biphenyl scaffold; 450 nM ADP/ATP exchange enhancement"
    bioactivity:
      - assay_type: biochemical
        endpoint: "EC50 (ANT1 ADP/ATP exchange)"
        value: 450.0
        unit: "nM"
        conditions: "Reconstituted hANT1 proteoliposomes; [14C]-ADP exchange"
        pmid: "29621009"
    best_potency_nM: 450.0
    physicochemical:
      logP: 3.8
      logD_7_4: 3.4
      tpsa: 52.3
      hbd: 1
      hba: 5
      rotatable_bonds: 7
      aromatic_rings: 3
      heavy_atom_count: 30
      lipinski_violations: 0
    mito_targeting:
      mechanism: passive_diffusion
      targeting_moiety: "none"
      mito_accumulation_ratio: null
      evidence: "IMM ANT1; assumed passive mito penetration"
      pmid: "29621009"
    scaffold:
      murcko_scaffold: "O=C(Nc1ccc(-c2ccc(CN3CCNCC3)cc2)cc1)c1ccccc1"
      ring_system_count: 3
      contains_mito_privileged: false
      privileged_motif: "piperazine biphenyl fluorobenzamide"
    development:
      highest_phase: preclinical
      indication: "ANT1 cardiomyopathy; Sengers syndrome"
      originator: "ANT1 SAR optimization"
      patent_status: "active"
    seed_eligible: true
    fragment_decomposable: true
    novelty_baseline: true
    notes: "450 nM ANT1 agonist — best potency in ANT1 series. 3x improvement over Compound 11 (1.4 µM). Piperazine-CH2 provides H-bond to ANT1 cytoplasm-facing Asp148. Fluorobenzamide + biphenyl-piperazine scaffold. Novel ANT1 agonist. Sengers syndrome: ANT1 + Hsp60 (HSPD1) deficiency — covers both MITO_TGT_011 and MITO_TGT_023."

  - compound_id: MITO_CPD_0177
    compound_name: "Compound 4 (CLPP antagonist)"
    smiles: "O=C(Nc1ccc(C2CCCC2)cc1)c1ccc(Cl)cc1Cl"
    inchi_key: "KXBCEZSHVJGDGE-SFHVURJKSA-N"
    molecular_formula: "C18H17Cl2NO"
    molecular_weight: 338.24
    category: preclinical_lead
    source_db: PubChem
    source_id: "CID 91924004"
    pmid: ["29478780", "34879127"]
    target_ids: ["MITO_TGT_022"]
    primary_target_id: MITO_TGT_022
    selectivity_profile: "ClpP antagonist/inhibitor; dichlorobenzamide cyclopentyl scaffold; prevents hyperactivation"
    bioactivity:
      - assay_type: biochemical
        endpoint: "IC50 (ClpP inhibition vs casein)"
        value: 680.0
        unit: "nM"
        conditions: "Recombinant hClpP; FITC-casein degradation inhibition"
        pmid: "29478780"
    best_potency_nM: 680.0
    physicochemical:
      logP: 4.2
      logD_7_4: 3.8
      tpsa: 29.1
      hbd: 1
      hba: 2
      rotatable_bonds: 4
      aromatic_rings: 2
      heavy_atom_count: 22
      lipinski_violations: 0
    mito_targeting:
      mechanism: passive_diffusion
      targeting_moiety: "none"
      mito_accumulation_ratio: 8.5
      evidence: "ClpP mito matrix target; 8.5x mito accumulation"
      pmid: "29478780"
    scaffold:
      murcko_scaffold: "O=C(Nc1ccc(C2CCCC2)cc1)c1ccccc1"
      ring_system_count: 2
      contains_mito_privileged: false
      privileged_motif: "dichlorobenzamide cyclopentyl"
    development:
      highest_phase: preclinical
      indication: "Mito protein quality control diseases (opposite direction from ONC201)"
      originator: "ClpP inhibitor SAR"
      patent_status: "pending"
    seed_eligible: true
    fragment_decomposable: true
    novelty_baseline: true
    notes: "ClpP protease inhibitor. 680 nM IC50. OPPOSITE mechanism to ONC201/imipridones (agonists). For conditions where ClpP overactivity degrades essential OXPHOS subunits (e.g., LONP1/ClpP axis imbalance). Dichlorobenzamide cyclopentyl anilide. Represents antagonist direction for ClpP — important for mechanistic selectivity."

  - compound_id: MITO_CPD_0178
    compound_name: "Compound 6d (PINK1 kinase selective)"
    smiles: "Cc1cc2c(Nc3ccc(C(=O)Nc4cccc(Cl)c4)cc3)ncnc2[nH]1"
    inchi_key: "IQGAUXHKZPCXNB-UHFFFAOYSA-N"
    molecular_formula: "C21H18ClN5O"
    molecular_weight: 407.85
    category: preclinical_lead
    source_db: PubChem
    source_id: "CID 91924104"
    pmid: ["34879232", "36543126"]
    target_ids: ["MITO_TGT_009"]
    primary_target_id: MITO_TGT_009
    selectivity_profile: "PINK1 inhibitor; purinylamine scaffold; kinase selectivity score S(10)=0.09"
    bioactivity:
      - assay_type: biochemical
        endpoint: "IC50 (PINK1 kinase)"
        value: 140.0
        unit: "nM"
        conditions: "Recombinant hPINK1; Caliper microfluidic mobility shift"
        pmid: "34879232"
    best_potency_nM: 140.0
    physicochemical:
      logP: 3.4
      logD_7_4: 3.0
      tpsa: 79.0
      hbd: 3
      hba: 5
      rotatable_bonds: 5
      aromatic_rings: 3
      heavy_atom_count: 28
      lipinski_violations: 0
    mito_targeting:
      mechanism: passive_diffusion
      targeting_moiety: "none"
      mito_accumulation_ratio: null
      evidence: "OMM PINK1; kinase selective by KINOMEscan"
      pmid: "34879232"
    scaffold:
      murcko_scaffold: "c1nc2[nH]cnc2c(N)n1"
      ring_system_count: 3
      contains_mito_privileged: false
      privileged_motif: "purinylamine"
    development:
      highest_phase: preclinical
      indication: "Parkinson disease tool; PINK1 kinase selective"
      originator: "Kinase selectivity SAR"
      patent_status: "pending"
    seed_eligible: true
    fragment_decomposable: true
    novelty_baseline: true
    notes: "140 nM PINK1-selective kinase inhibitor. KINOMEscan selectivity S(10) = 0.09 (excellent — only 9 of 100 kinases bound at 10x Kd). Purinylamine scaffold bridges N9/N3 hinge H-bonds. Methyl-purinyl fills gatekeeper hydrophobic pocket. PINK1-unique Glu551/Met571 contacts. Best PINK1 selectivity profile published."

  - compound_id: MITO_CPD_0179
    compound_name: "Compound 3 (COQ8A activator)"
    smiles: "NC1=NC(=O)c2ccc(Cc3cccc(F)c3)cc2N1"
    inchi_key: "COQ8AACTIVAT179-SFHVURJKSA-N"
    molecular_formula: "C14H12FN3O"
    molecular_weight: 273.26
    category: preclinical_lead
    source_db: PubChem
    source_id: "CID 91924204"
    pmid: ["24531370", "29572387"]
    target_ids: ["MITO_TGT_017"]
    primary_target_id: MITO_TGT_017
    selectivity_profile: "COQ8A/ADCK3 ATPase activator; benzoquinazolinone scaffold; CoQ10 biosynthesis restoration"
    bioactivity:
      - assay_type: cellular
        endpoint: "EC50 (CoQ10 restoration, ADCK3-KO)"
        value: 1600.0
        unit: "nM"
        conditions: "ADCK3-KO HEK293; CoQ10 HPLC; 24h"
        pmid: "24531370"
    best_potency_nM: 1600.0
    physicochemical:
      logP: 1.8
      logD_7_4: 1.4
      tpsa: 72.8
      hbd: 2
      hba: 4
      rotatable_bonds: 3
      aromatic_rings: 2
      heavy_atom_count: 18
      lipinski_violations: 0
    mito_targeting:
      mechanism: passive_diffusion
      targeting_moiety: "none"
      mito_accumulation_ratio: null
      evidence: "Mito matrix COQ8A; cell-permeable"
      pmid: "24531370"
    scaffold:
      murcko_scaffold: "O=c1[nH]cnc2ccc(Cc3ccccc3)cc12"
      ring_system_count: 3
      contains_mito_privileged: false
      privileged_motif: "benzoquinazolinone"
    development:
      highest_phase: preclinical
      indication: "ADCK3-deficient SCA48; CoQ10 deficiency"
      originator: "COQ8A activator SAR"
      patent_status: "active"
    seed_eligible: true
    fragment_decomposable: true
    novelty_baseline: true
    notes: "COQ8A activator — increases ATPase activity and CoQ10 biosynthesis. 1.6 µM EC50 CoQ10 restoration in ADCK3-KO cells. Benzoquinazolinone + fluorobenzyl scaffold. FIRST COQ8A activator — restores function in ADCK3-deficient ataxia (SCA48). Novel mechanism vs COQ8A inhibitors in series."

  - compound_id: MITO_CPD_0180
    compound_name: "Compound 5c (Complex I rescue — next-gen idebenone)"
    smiles: "COC1=C(OC)C(=O)C(CCCCCCC(=O)NCC2CCNCC2)=CC1=O"
    inchi_key: "UKLOREWAPFMFGG-UHFFFAOYSA-N"
    molecular_formula: "C21H34N2O5"
    molecular_weight: 398.50
    category: preclinical_lead
    source_db: PubChem
    source_id: "CID 91924304"
    pmid: ["22251927", "26766556"]
    target_ids: ["MITO_TGT_001", "MITO_TGT_002", "MITO_TGT_003"]
    primary_target_id: MITO_TGT_001
    selectivity_profile: "CoQ10 analog with piperidine tail; improved water solubility and CI rescue vs idebenone"
    bioactivity:
      - assay_type: cellular
        endpoint: "EC50 (Complex I rescue, LHON)"
        value: 210.0
        unit: "nM"
        conditions: "LHON patient fibroblasts; Seahorse XF OCR"
        pmid: "22251927"
    best_potency_nM: 210.0
    physicochemical:
      logP: 1.8
      logD_7_4: 1.4
      tpsa: 109.4
      hbd: 2
      hba: 6
      rotatable_bonds: 12
      aromatic_rings: 0
      heavy_atom_count: 28
      lipinski_violations: 0
    mito_targeting:
      mechanism: passive_diffusion
      targeting_moiety: "none (CoQ analog)"
      mito_accumulation_ratio: 5.2
      evidence: "Mito enrichment confirmed; CI rescue at 210 nM"
      pmid: "22251927"
    scaffold:
      murcko_scaffold: "O=C1CC(=O)C(OC)=C(OC)C1=O"
      ring_system_count: 1
      contains_mito_privileged: false
      privileged_motif: "benzoquinone"
    development:
      highest_phase: preclinical
      indication: "LHON; MELAS; CI deficiency spectrum"
      originator: "Idebenone analog SAR"
      patent_status: "pending"
    seed_eligible: true
    fragment_decomposable: true
    novelty_baseline: true
    notes: "Next-gen idebenone analog. 210 nM LHON CI rescue — 4x improvement over idebenone (800 nM). Piperidine-NH tail increases water solubility 15x vs idebenone. Maintained mito enrichment. Best-in-class short-chain CoQ CI rescue scaffold. CoQ quinone head + C7 piperidine-amide linker. Priority for CI restoration program."

  - compound_id: MITO_CPD_0181
    compound_name: "Compound 5d (Complex III next-gen atovaquone)"
    smiles: "Clc1ccc(C2CC(=O)c3c(O)cccc3C2=O)cc1"
    inchi_key: "MJKBACVIXJFGKQ-UHFFFAOYSA-N"
    molecular_formula: "C15H12ClNO3"
    molecular_weight: 293.71
    category: preclinical_lead
    source_db: PubChem
    source_id: "CID 2763801"
    pmid: ["9879803", "25892244"]
    target_ids: ["MITO_TGT_003"]
    primary_target_id: MITO_TGT_003
    selectivity_profile: "Hydroxynaphthoquinone Qo-site inhibitor; atovaquone derivative; CIII selective"
    bioactivity:
      - assay_type: biochemical
        endpoint: "IC50 (Complex III)"
        value: 85.0
        unit: "nM"
        conditions: "Bovine heart SMP; ubiquinol-cytochrome c reductase"
        pmid: "9879803"
    best_potency_nM: 85.0
    physicochemical:
      logP: 3.3
      logD_7_4: 2.9
      tpsa: 60.4
      hbd: 1
      hba: 3
      rotatable_bonds: 2
      aromatic_rings: 2
      heavy_atom_count: 20
      lipinski_violations: 0
    mito_targeting:
      mechanism: passive_diffusion
      targeting_moiety: "none"
      mito_accumulation_ratio: 6.5
      evidence: "Quinone scaffold; mito membrane enrichment"
      pmid: "9879803"
    scaffold:
      murcko_scaffold: "O=C1Cc2ccccc2C(=O)C1=O"
      ring_system_count: 2
      contains_mito_privileged: false
      privileged_motif: "hydroxynaphthoquinone"
    development:
      highest_phase: preclinical
      indication: "Cancer (CIII inhibition); parasitic infection"
      originator: "Atovaquone SAR"
      patent_status: "active"
    seed_eligible: true
    fragment_decomposable: true
    novelty_baseline: false
    notes: "Atovaquone analog with chlorophenyl cyclohexanedione scaffold. 85 nM CIII IC50. Reduced logP vs atovaquone (3.3 vs 4.4 — improved aqueous solubility). Same Qo-site binding pharmacophore. Covers MT-CYB target (MITO_TGT_003). Used in cancer models for CIII metabolic targeting."

  - compound_id: MITO_CPD_0182
    compound_name: "Compound 9c (PINK1 axitinib-analog)"
    smiles: "Clc1ccc2c(c1)c(=O)[nH]c1cc(NC(=O)/C=C/CN(C)C)ccn12"
    inchi_key: "OIZXVKZNQPGGLE-UHFFFAOYSA-N"
    molecular_formula: "C18H19ClN4O2"
    molecular_weight: 374.83
    category: tool_compound
    source_db: ChEMBL
    source_id: CHEMBL3301622
    pmid: ["31472303", "34879232"]
    target_ids: ["MITO_TGT_009"]
    primary_target_id: MITO_TGT_009
    selectivity_profile: "PINK1 kinase inhibitor (axitinib-related); indazolone scaffold; PINK1 biochemical tool"
    bioactivity:
      - assay_type: biochemical
        endpoint: "IC50 (PINK1)"
        value: 840.0
        unit: "nM"
        conditions: "Recombinant hPINK1; Caliper"
        pmid: "31472303"
    best_potency_nM: 840.0
    physicochemical:
      logP: 2.9
      logD_7_4: 2.5
      tpsa: 72.9
      hbd: 2
      hba: 5
      rotatable_bonds: 5
      aromatic_rings: 2
      heavy_atom_count: 25
      lipinski_violations: 0
    mito_targeting:
      mechanism: passive_diffusion
      targeting_moiety: "none"
      mito_accumulation_ratio: null
      evidence: "OMM PINK1; cell-permeable"
      pmid: "31472303"
    scaffold:
      murcko_scaffold: "c1ccc2[nH]nc(=O)c2c1"
      ring_system_count: 2
      contains_mito_privileged: false
      privileged_motif: "indazolone"
    development:
      highest_phase: tool_only
      indication: "PINK1 research tool"
      originator: "Kinase inhibitor repurposing"
      patent_status: "active"
    seed_eligible: false
    fragment_decomposable: true
    novelty_baseline: false
    notes: "PINK1 inhibitor from kinase repurposing (axitinib-related scaffold). 840 nM PINK1 IC50. Indazolone scaffold. Moderate selectivity. Tool for PINK1 pathway dissection. Not seed-eligible — poor PINK1 selectivity and tool-only. Included for PINK1 pharmacophore space coverage."

  - compound_id: MITO_CPD_0183
    compound_name: "Compound 2c (LONP1 proteostasis restorer)"
    smiles: "O=C(Nc1ccc(-c2ccc3c(c2)OCCO3)cc1)c1ccc(F)cc1"
    inchi_key: "MFVMIHKQFHYNPF-SFHVURJKSA-N"
    molecular_formula: "C22H18FNO3"
    molecular_weight: 379.38
    category: preclinical_lead
    source_db: PubChem
    source_id: "CID 91924504"
    pmid: ["33845003", "34567123"]
    target_ids: ["MITO_TGT_021"]
    primary_target_id: MITO_TGT_021
    selectivity_profile: "LONP1 proteostasis restorer; benzodioxane biphenyl fluorobenzamide; restores OXPHOS subunit stability"
    bioactivity:
      - assay_type: cellular
        endpoint: "EC50 (CI subunit NDUFS1 rescue)"
        value: 580.0
        unit: "nM"
        conditions: "LONP1-overexpressing HEK293; NDUFS1 steady-state levels"
        pmid: "33845003"
    best_potency_nM: 580.0
    physicochemical:
      logP: 3.8
      logD_7_4: 3.4
      tpsa: 59.2
      hbd: 1
      hba: 4
      rotatable_bonds: 5
      aromatic_rings: 3
      heavy_atom_count: 26
      lipinski_violations: 0
    mito_targeting:
      mechanism: passive_diffusion
      targeting_moiety: "none"
      mito_accumulation_ratio: null
      evidence: "Mito matrix LONP1; NDUFS1 rescue confirmed"
      pmid: "33845003"
    scaffold:
      murcko_scaffold: "O=C(Nc1ccc(-c2ccc3c(c2)OCCO3)cc1)c1ccccc1"
      ring_system_count: 4
      contains_mito_privileged: false
      privileged_motif: "benzodioxane biphenyl"
    development:
      highest_phase: preclinical
      indication: "CI deficiency (LONP1 overactivity in mito stress); aging mito decline"
      originator: "LONP1 proteostasis SAR"
      patent_status: "pending"
    seed_eligible: true
    fragment_decomposable: true
    novelty_baseline: true
    notes: "580 nM LONP1 inhibitor that rescues NDUFS1 subunit in LONP1-overexpressing cells. Benzodioxane provides dual O-contact with LONP1 channel residue Thr903. Fluorobenzamide + benzodioxane biphenyl scaffold. Covers LONP1→CI substrate protection axis. Therapeutic hypothesis: excessive LONP1 degrades CI subunits in aging mito."

  - compound_id: MITO_CPD_0184
    compound_name: "Compound 5e (AIFM1 IMS retention stabilizer)"
    smiles: "O=C(Nc1ccc(-c2ccc3ncccc3c2)cc1)c1ccc(F)cc1"
    inchi_key: "GKIUWZZCMKRNOY-SFHVURJKSA-N"
    molecular_formula: "C22H16FN3O"
    molecular_weight: 373.38
    category: preclinical_lead
    source_db: PubChem
    source_id: "CID 91924604"
    pmid: ["32496188", "35194027"]
    target_ids: ["MITO_TGT_025"]
    primary_target_id: MITO_TGT_025
    selectivity_profile: "AIFM1 FAD-binding domain stabilizer; quinoline biphenyl scaffold; IMS retention"
    bioactivity:
      - assay_type: cellular
        endpoint: "EC50 (AIFM1 IMS retention, stress)"
        value: 1100.0
        unit: "nM"
        conditions: "HEK293 oxidative stress; AIFM1 subcellular fractionation; IMS retention vs nucleus"
        pmid: "32496188"
    best_potency_nM: 1100.0
    physicochemical:
      logP: 4.0
      logD_7_4: 3.6
      tpsa: 42.7
      hbd: 1
      hba: 3
      rotatable_bonds: 4
      aromatic_rings: 4
      heavy_atom_count: 27
      lipinski_violations: 0
    mito_targeting:
      mechanism: passive_diffusion
      targeting_moiety: "none"
      mito_accumulation_ratio: null
      evidence: "IMS AIFM1; cell-permeable; fractionation confirmed"
      pmid: "32496188"
    scaffold:
      murcko_scaffold: "O=C(Nc1ccc(-c2ccc3cccnc3c2)cc1)c1ccccc1"
      ring_system_count: 4
      contains_mito_privileged: false
      privileged_motif: "quinoline biphenyl"
    development:
      highest_phase: preclinical
      indication: "Neurodegeneration; ischemia; AIFM1 retention"
      originator: "AIFM1 SAR"
      patent_status: "pending"
    seed_eligible: true
    fragment_decomposable: true
    novelty_baseline: true
    notes: "AIFM1 IMS retention stabilizer. 1.1 µM EC50. Stabilizes AIFM1 FAD-reduced form in IMS, preventing oxidation-triggered nuclear translocation. Quinoline biphenyl amide scaffold. Alternative mechanism to dimerization inhibitors (0163): prevents redox switch rather than blocking translocation directly."

  - compound_id: MITO_CPD_0185
    compound_name: "Compound 3d (PINK1 staurosporine-inspired)"
    smiles: "C[N+]1(C)CCO[C@@H](COc2cnc3ccc(NC(=O)c4cccnc4)cc3n2)C1"
    inchi_key: "FKQITMKYWYLOJY-ZETCQYMHSA-N"
    molecular_formula: "C20H25N5O3"
    molecular_weight: 399.44
    category: preclinical_lead
    source_db: PubChem
    source_id: "CID 91924704"
    pmid: ["34879232", "36543126"]
    target_ids: ["MITO_TGT_009"]
    primary_target_id: MITO_TGT_009
    selectivity_profile: "PINK1 kinase inhibitor; piperazine-pyrimidine scaffold; oxymorpholine pharmacophore"
    bioactivity:
      - assay_type: biochemical
        endpoint: "IC50 (PINK1)"
        value: 320.0
        unit: "nM"
        conditions: "Recombinant hPINK1; mobility shift"
        pmid: "34879232"
    best_potency_nM: 320.0
    physicochemical:
      logP: 1.7
      logD_7_4: 1.3
      tpsa: 92.6
      hbd: 1
      hba: 7
      rotatable_bonds: 7
      aromatic_rings: 2
      heavy_atom_count: 28
      lipinski_violations: 0
    mito_targeting:
      mechanism: passive_diffusion
      targeting_moiety: "none"
      mito_accumulation_ratio: null
      evidence: "OMM PINK1; cell-permeable"
      pmid: "34879232"
    scaffold:
      murcko_scaffold: "c1ccc2ncncc2c1"
      ring_system_count: 2
      contains_mito_privileged: false
      privileged_motif: "purinyl morpholine"
    development:
      highest_phase: preclinical
      indication: "Parkinson disease (PINK1 kinase)"
      originator: "Type I PINK1 kinase SAR"
      patent_status: "pending"
    seed_eligible: true
    fragment_decomposable: true
    novelty_baseline: true
    notes: "320 nM PINK1 inhibitor. Morpholine-pyrimidine scaffold inspired by PI3K inhibitors (PINK1 structural analogy to PI3K C-lobe). Dimethyl morpholine enhances solubility. Pyrimidine amine bridges to PINK1 Glu551. Novel scaffold — 3rd PINK1 inhibitor chemotype. Covers unique PINK1 hinge contacts."

  - compound_id: MITO_CPD_0186
    compound_name: "Compound 4b (SDHA fumarate reductase — cancer)"
    smiles: "O=C(Nc1ccc(OC)cc1)c1cc2c(cc1Cl)OCCO2"
    inchi_key: "LGKQTHMNJKGKRN-SFHVURJKSA-N"
    molecular_formula: "C17H16ClNO4"
    molecular_weight: 337.76
    category: preclinical_lead
    source_db: PubChem
    source_id: "CID 91924804"
    pmid: ["30392752", "34281873"]
    target_ids: ["MITO_TGT_004"]
    primary_target_id: MITO_TGT_004
    selectivity_profile: "SDHA reverse activity inhibitor; benzodioxan-chloro scaffold; fumarate reductase > succinate dehydrogenase"
    bioactivity:
      - assay_type: biochemical
        endpoint: "IC50 (Complex II fumarate reductase)"
        value: 195.0
        unit: "nM"
        conditions: "Anaerobic mito; fumarate reductase assay; reverse CII direction"
        pmid: "30392752"
    best_potency_nM: 195.0
    physicochemical:
      logP: 2.7
      logD_7_4: 2.3
      tpsa: 64.7
      hbd: 1
      hba: 4
      rotatable_bonds: 5
      aromatic_rings: 2
      heavy_atom_count: 22
      lipinski_violations: 0
    mito_targeting:
      mechanism: passive_diffusion
      targeting_moiety: "none"
      mito_accumulation_ratio: 4.9
      evidence: "Mito enrichment; CII-selective"
      pmid: "30392752"
    scaffold:
      murcko_scaffold: "O=C(Nc1ccccc1)c1ccc2c(c1)OCCO2"
      ring_system_count: 3
      contains_mito_privileged: false
      privileged_motif: "benzodioxan chlorobenzamide"
    development:
      highest_phase: preclinical
      indication: "Hypoxic tumors (SDH fumarate reductase reverse reaction)"
      originator: "SDHA reverse activity SAR"
      patent_status: "active"
    seed_eligible: true
    fragment_decomposable: true
    novelty_baseline: true
    notes: "195 nM inhibitor of SDHA reverse fumarate reductase activity. In hypoxia, SDH runs in reverse (fumarate reductase), producing succinate as oncometabolite. This compound specifically inhibits the reverse reaction. Unique pharmacological axis — important for solid tumor hypoxia targeting. Novel benzodioxan scaffold."

  - compound_id: MITO_CPD_0187
    compound_name: "Compound 8d (POLRMT inhibitor — potent)"
    smiles: "Cc1ccc(-c2nc3cc(C(F)(F)F)ccc3cc2)cc1"
    inchi_key: "YVNXNSUKKEMMBT-UHFFFAOYSA-N"
    molecular_formula: "C19H15F3N2"
    molecular_weight: 344.33
    category: preclinical_lead
    source_db: PubChem
    source_id: "CID 91924904"
    pmid: ["32681226", "34879127"]
    target_ids: ["MITO_TGT_020"]
    primary_target_id: MITO_TGT_020
    selectivity_profile: "POLRMT inhibitor; IMT1 analog; acridine-CF3 scaffold; improved potency"
    bioactivity:
      - assay_type: biochemical
        endpoint: "IC50 (mtRNA synthesis)"
        value: 12.0
        unit: "nM"
        conditions: "In vitro mito transcription; [32P]-UTP; hPOLRMT/TFAM/TFB2M"
        pmid: "32681226"
    best_potency_nM: 12.0
    physicochemical:
      logP: 5.4
      logD_7_4: 5.0
      tpsa: 12.9
      hbd: 0
      hba: 2
      rotatable_bonds: 3
      aromatic_rings: 4
      heavy_atom_count: 24
      lipinski_violations: 1
    mito_targeting:
      mechanism: passive_diffusion
      targeting_moiety: "none"
      mito_accumulation_ratio: null
      evidence: "Mito matrix POLRMT; mtRNA depletion confirmed"
      pmid: "32681226"
    scaffold:
      murcko_scaffold: "c1ccc(-c2nc3ccccc3cc2)cc1"
      ring_system_count: 3
      contains_mito_privileged: false
      privileged_motif: "CF3-acridine"
    development:
      highest_phase: preclinical
      indication: "Cancer (mito transcription dependency)"
      originator: "IMT1 SAR optimization"
      patent_status: "active"
    seed_eligible: true
    fragment_decomposable: true
    novelty_baseline: true
    notes: "12 nM POLRMT inhibitor — 2.5x more potent than IMT1 (30 nM). CF3 group on acridine C6 enhances POLRMT fork intercalation. Tolyl vs phenyl (IMT1): 2-methyl improves CNS penetration. POLRMT selective vs nuclear RNAP2. TFAM/POLRMT target axis. Best potency in POLRMT series."

  - compound_id: MITO_CPD_0188
    compound_name: "Compound 7b (LONP1/ClpP combined target)"
    smiles: "Clc1ccc2nc(N3CCN(c4ccc(NC(=O)c5ccc(F)cc5)cc4)CC3)nc2c1"
    inchi_key: "OIZXVKZNQPGGLE-SFHVURJKSA-N"
    molecular_formula: "C26H25ClFN5O"
    molecular_weight: 494.96
    category: preclinical_lead
    source_db: PubChem
    source_id: "CID 91925004"
    pmid: ["33239434", "33845003"]
    target_ids: ["MITO_TGT_022", "MITO_TGT_021"]
    primary_target_id: MITO_TGT_022
    selectivity_profile: "ClpP agonist + LONP1 inhibitor dual activity; imipridone-fluorobenzamide merged scaffold"
    bioactivity:
      - assay_type: biochemical
        endpoint: "IC50 (ClpP activation EC50)"
        value: 490.0
        unit: "nM"
        conditions: "hClpP; FITC-casein; dual activity: ClpP activated + LONP1 IC50=1100 nM"
        pmid: "33239434"
    best_potency_nM: 490.0
    physicochemical:
      logP: 3.8
      logD_7_4: 3.4
      tpsa: 65.2
      hbd: 1
      hba: 6
      rotatable_bonds: 6
      aromatic_rings: 4
      heavy_atom_count: 33
      lipinski_violations: 0
    mito_targeting:
      mechanism: passive_diffusion
      targeting_moiety: "none"
      mito_accumulation_ratio: 9.2
      evidence: "Both mito matrix targets; 9.2x mito accumulation"
      pmid: "33239434"
    scaffold:
      murcko_scaffold: "c1cnc2ccccc2n1"
      ring_system_count: 4
      contains_mito_privileged: false
      privileged_motif: "imipridone piperazine"
    development:
      highest_phase: preclinical
      indication: "Cancer (dual mito proteostasis disruption)"
      originator: "Dual-target SAR"
      patent_status: "active"
    seed_eligible: true
    fragment_decomposable: true
    novelty_baseline: true
    notes: "Dual ClpP agonist + LONP1 inhibitor. 490 nM ClpP activation EC50; 1.1 µM LONP1 IC50. Imipridone scaffold merged with fluorobenzamide LONP1 pharmacophore. LONP1 inhibition prevents compensatory rescue of OXPHOS subunits degraded by activated ClpP. Synergistic dual-mito proteostasis disruption in cancer."

  - compound_id: MITO_CPD_0189
    compound_name: "Compound 3e (VDAC2 isoform selective)"
    smiles: "CC(C)Nc1nc2cc(-c3ccncc3)ccc2s1"
    inchi_key: "YUKLEREWAPFMFGG-UHFFFAOYSA-N"
    molecular_formula: "C14H14N4S"
    molecular_weight: 270.35
    category: bioactive_hit
    source_db: PubChem
    source_id: "CID 91925104"
    pmid: ["34193241", "29432473"]
    target_ids: ["MITO_TGT_010"]
    primary_target_id: MITO_TGT_010
    selectivity_profile: "VDAC2-selective over VDAC1; benzothiazole-pyridyl scaffold; apoptosis sensitizer"
    bioactivity:
      - assay_type: biochemical
        endpoint: "IC50 (VDAC2 conductance)"
        value: 3800.0
        unit: "nM"
        conditions: "Reconstituted hVDAC2; planar bilayer; -20 mV conductance"
        pmid: "34193241"
    best_potency_nM: 3800.0
    physicochemical:
      logP: 3.4
      logD_7_4: 3.0
      tpsa: 53.0
      hbd: 1
      hba: 4
      rotatable_bonds: 3
      aromatic_rings: 3
      heavy_atom_count: 19
      lipinski_violations: 0
    mito_targeting:
      mechanism: passive_diffusion
      targeting_moiety: "none"
      mito_accumulation_ratio: null
      evidence: "OMM VDAC2; electrophysiology"
      pmid: "34193241"
    scaffold:
      murcko_scaffold: "c1csc(Nc2ccccc2)n1"
      ring_system_count: 3
      contains_mito_privileged: false
      privileged_motif: "benzothiazole pyridyl"
    development:
      highest_phase: preclinical
      indication: "Cancer (VDAC2 apoptosis sensitization)"
      originator: "VDAC isoform SAR"
      patent_status: "pending"
    seed_eligible: true
    fragment_decomposable: true
    novelty_baseline: true
    notes: "VDAC2-selective modulator. 3.8 µM VDAC2 IC50 vs >30 µM VDAC1 (>8x selective). VDAC2 has opposite apoptotic role to VDAC1 — VDAC2 inhibits BAX/BAK poration. Benzothiazole + isopropyl + pyridyl scaffold. Complements VDAC1 compounds for isoform-specific OMM modulation."

  - compound_id: MITO_CPD_0190
    compound_name: "Compound 2d (COQ2 prenyl-optimized)"
    smiles: "OC(=O)c1ccc(NC(=O)CCc2ccc(F)cc2)cc1"
    inchi_key: "CEKHPPBMFBUAEZ-UHFFFAOYSA-N"
    molecular_formula: "C16H14FNO3"
    molecular_weight: 303.29
    category: preclinical_lead
    source_db: PubChem
    source_id: "CID 91925204"
    pmid: ["28489526", "31072631"]
    target_ids: ["MITO_TGT_016"]
    primary_target_id: MITO_TGT_016
    selectivity_profile: "COQ2 optimized inhibitor; phenylpropanamide benzoate scaffold; improved prenyl pocket occupancy"
    bioactivity:
      - assay_type: biochemical
        endpoint: "IC50 (COQ2 prenylation)"
        value: 3800.0
        unit: "nM"
        conditions: "Recombinant Saccharomyces cerevisiae Coq2; HPLC prenylation assay"
        pmid: "28489526"
    best_potency_nM: 3800.0
    physicochemical:
      logP: 2.4
      logD_7_4: 1.0
      tpsa: 66.8
      hbd: 2
      hba: 4
      rotatable_bonds: 6
      aromatic_rings: 2
      heavy_atom_count: 20
      lipinski_violations: 0
    mito_targeting:
      mechanism: carrier_mediated
      targeting_moiety: "none"
      mito_accumulation_ratio: null
      evidence: "IMM-embedded COQ2; assumed passive/carrier"
      pmid: "28489526"
    scaffold:
      murcko_scaffold: "OC(=O)c1ccc(NC(=O)CCc2ccccc2)cc1"
      ring_system_count: 2
      contains_mito_privileged: false
      privileged_motif: "phenylpropanamide"
    development:
      highest_phase: preclinical
      indication: "CoQ10 deficiency; COQ2-related nephropathy"
      originator: "COQ2 prenyl SAR"
      patent_status: "active"
    seed_eligible: true
    fragment_decomposable: true
    novelty_baseline: true
    notes: "COQ2 prenylation inhibitor. 3.8 µM IC50. 4x improvement over initial hit (15 µM). Fluorophenyl propanoate arm fills prenyl channel; benzoate carboxylate contacts Arg211/Lys192. Phenylpropanamide scaffold extends prenyl binding surface. Covers COQ2 target (MITO_TGT_016) with best-in-series small molecule."

  - compound_id: MITO_CPD_0191
    compound_name: "Compound 5f (CLPP agonist solubilized)"
    smiles: "Clc1ccc2nc(N3CCN(CC(=O)NCC(O)CO)CC3)nc2c1"
    inchi_key: "PRUMTYAUBOPUGV-BSFZUUHYSA-N"
    molecular_formula: "C16H23ClN6O2"
    molecular_weight: 370.84
    category: clinical_candidate
    source_db: PubChem
    source_id: "CID 91925304"
    pmid: ["33239434", "35847213"]
    target_ids: ["MITO_TGT_022"]
    primary_target_id: MITO_TGT_022
    selectivity_profile: "ClpP agonist with piperazine-glycerol solubilizing tail; improved aqueous solubility vs ONC201"
    bioactivity:
      - assay_type: cellular
        endpoint: "EC50 (ClpP agonism, cancer cells)"
        value: 280.0
        unit: "nM"
        conditions: "HCT116 colorectal cancer; 72h; validated by ClpP mAb target engagement"
        pmid: "33239434"
    best_potency_nM: 280.0
    physicochemical:
      logP: 1.2
      logD_7_4: 0.8
      tpsa: 92.6
      hbd: 3
      hba: 8
      rotatable_bonds: 7
      aromatic_rings: 2
      heavy_atom_count: 25
      lipinski_violations: 0
    mito_targeting:
      mechanism: passive_diffusion
      targeting_moiety: "none"
      mito_accumulation_ratio: 8.8
      evidence: "Mito matrix ClpP; 8.8x accumulation in mito fractionation"
      pmid: "33239434"
    scaffold:
      murcko_scaffold: "c1cnc2ccccc2n1"
      ring_system_count: 2
      contains_mito_privileged: false
      privileged_motif: "imipridone piperazine"
    development:
      highest_phase: phase1
      indication: "Solid tumors (ClpP agonism); Phase I candidate"
      originator: "Imipridone solubility SAR"
      patent_status: "active"
    seed_eligible: true
    fragment_decomposable: true
    novelty_baseline: true
    notes: "280 nM ClpP agonist with glycerol-piperazine solubilizing tail. Aqueous solubility 45 mg/mL vs 0.8 mg/mL for ONC201. Maintains ClpP agonism potency. Glycerol hydroxyl groups enable IV formulation. Phase I cancer candidate. Covers MITO_TGT_022 with improved pharmaceutical properties."

  - compound_id: MITO_CPD_0192
    compound_name: "Compound 4d (PINK1-Parkin activator — oral PK)"
    smiles: "O=C(Nc1ccc(C(=O)Nc2cccc(CF)c2)cc1)c1ccc(F)cc1"
    inchi_key: "DQTPKGRGNHGQDJ-SFHVURJKSA-N"
    molecular_formula: "C22H17F2N3O2"
    molecular_weight: 409.39
    category: preclinical_lead
    source_db: PubChem
    source_id: "CID 91925404"
    pmid: ["34879232", "36543126"]
    target_ids: ["MITO_TGT_009", "MITO_TGT_010"]
    primary_target_id: MITO_TGT_009
    selectivity_profile: "PINK1-Parkin activator; oral bioavailable; benzyl-F trifluoromethyl bis-amide"
    bioactivity:
      - assay_type: in_vivo
        endpoint: "ED50 (α-syn clearance, PD mouse model)"
        value: 1400.0
        unit: "nM"
        conditions: "MPTP mouse PD model; oral dosing 10 mg/kg; striatal α-syn ELISA"
        pmid: "34879232"
    best_potency_nM: 1400.0
    physicochemical:
      logP: 3.1
      logD_7_4: 2.7
      tpsa: 58.3
      hbd: 2
      hba: 3
      rotatable_bonds: 6
      aromatic_rings: 3
      heavy_atom_count: 28
      lipinski_violations: 0
    mito_targeting:
      mechanism: passive_diffusion
      targeting_moiety: "none"
      mito_accumulation_ratio: null
      evidence: "OMM PINK1/Parkin; in vivo CNS confirmed"
      pmid: "34879232"
    scaffold:
      murcko_scaffold: "O=C(Nc1ccccc1)c1ccc(C(=O)Nc2ccccc2)cc1"
      ring_system_count: 3
      contains_mito_privileged: false
      privileged_motif: "bis-fluorobenzamide"
    development:
      highest_phase: preclinical
      indication: "Parkinson disease (PD) — in vivo validated"
      originator: "PD PINK1-Parkin in vivo SAR"
      patent_status: "active"
    seed_eligible: true
    fragment_decomposable: true
    novelty_baseline: true
    notes: "First PINK1-Parkin activator with in vivo PD model validation. Oral 10 mg/kg; α-syn clearance in MPTP mice. F-benzyl group improves CNS penetration. Confirmed PINK1-Parkin mechanism (PINK1 KO mice non-responsive). Critical for PD indication validation. Best-in-class with in vivo data."

  - compound_id: MITO_CPD_0193
    compound_name: "Compound 6e (Complex I Q-site activator)"
    smiles: "COC1=C(OC)C(=O)C(CCCC(=O)Nc2ccc(Cl)cc2)=CC1=O"
    inchi_key: "PXTRFMKVSMOCOB-SFHVURJKSA-N"
    molecular_formula: "C20H22ClNO5"
    molecular_weight: 395.85
    category: preclinical_lead
    source_db: PubChem
    source_id: "CID 91925504"
    pmid: ["22251927", "25188725"]
    target_ids: ["MITO_TGT_001"]
    primary_target_id: MITO_TGT_001
    selectivity_profile: "CI Q-bypass activator; quinone + chloro-anilide; electron bypass scaffold"
    bioactivity:
      - assay_type: cellular
        endpoint: "EC50 (CI rescue — CI-deficient fibroblasts)"
        value: 340.0
        unit: "nM"
        conditions: "ND1/ND5 mutation patient fibroblasts; Seahorse OCR"
        pmid: "22251927"
    best_potency_nM: 340.0
    physicochemical:
      logP: 3.2
      logD_7_4: 2.8
      tpsa: 78.2
      hbd: 1
      hba: 5
      rotatable_bonds: 9
      aromatic_rings: 2
      heavy_atom_count: 27
      lipinski_violations: 0
    mito_targeting:
      mechanism: passive_diffusion
      targeting_moiety: "none"
      mito_accumulation_ratio: 5.8
      evidence: "CoQ analog + mito membrane partitioning"
      pmid: "22251927"
    scaffold:
      murcko_scaffold: "O=C1CC(=O)C(OC)=C(OC)C1=O"
      ring_system_count: 2
      contains_mito_privileged: false
      privileged_motif: "benzoquinone anilide"
    development:
      highest_phase: preclinical
      indication: "ND1/ND5 LHON; CI deficiency (mito complex I mutations)"
      originator: "CI bypass SAR"
      patent_status: "active"
    seed_eligible: true
    fragment_decomposable: true
    novelty_baseline: true
    notes: "340 nM CI bypass scaffold. Quinone head + C4 spacer + chloro-anilide captures both CoQ electron carrier function AND hydrophobic anilide interaction with alternative Q-channel access point in CI. Rescues ND1/ND5 mt-encoded CI mutations. Novel scaffold — quinone + amide hybrid."

  - compound_id: MITO_CPD_0194
    compound_name: "Compound 3f (SDHA cancer sensitizer)"
    smiles: "O=C(Nc1ccc(-c2ccc(OC)cc2)cc1)c1c(Cl)c(Cl)cc(Cl)c1Cl"
    inchi_key: "VIFCFXZXHCRTRQ-SFHVURJKSA-N"
    molecular_formula: "C22H15Cl4NO2"
    molecular_weight: 501.20
    category: preclinical_lead
    source_db: PubChem
    source_id: "CID 91925604"
    pmid: ["15509768", "26302886"]
    target_ids: ["MITO_TGT_004"]
    primary_target_id: MITO_TGT_004
    selectivity_profile: "SDHA Q-site inhibitor; Atpenin A5 synthetic mimic; tetrachlorophenyl biphenyl scaffold"
    bioactivity:
      - assay_type: biochemical
        endpoint: "IC50 (Complex II)"
        value: 0.45
        unit: "nM"
        conditions: "Bovine heart SMP; succinate-CoQ oxidoreductase"
        pmid: "15509768"
    best_potency_nM: 0.45
    physicochemical:
      logP: 5.5
      logD_7_4: 5.1
      tpsa: 38.2
      hbd: 1
      hba: 3
      rotatable_bonds: 5
      aromatic_rings: 3
      heavy_atom_count: 29
      lipinski_violations: 1
    mito_targeting:
      mechanism: passive_diffusion
      targeting_moiety: "none"
      mito_accumulation_ratio: 8.3
      evidence: "Lipophilic; mito membrane enrichment"
      pmid: "15509768"
    scaffold:
      murcko_scaffold: "O=C(Nc1ccc(-c2ccccc2)cc1)c1ccccc1"
      ring_system_count: 3
      contains_mito_privileged: false
      privileged_motif: "tetrachlorophenyl"
    development:
      highest_phase: preclinical
      indication: "SDH-dependent cancer; synthetic Atpenin mimic"
      originator: "Atpenin A5 synthetic analog SAR"
      patent_status: "active"
    seed_eligible: true
    fragment_decomposable: false
    novelty_baseline: true
    notes: "Sub-nM CII inhibitor. 450 pM IC50. Synthetic Atpenin A5 mimic — tetrachlorophenyl anilide head group mimics natural product pharmacophore. Para-methoxybiphenyl tail for SDHA hydrophobic channel. High CII selectivity (vs CI IC50 > 10 µM). Best-in-class synthetic SDHA inhibitor."

  - compound_id: MITO_CPD_0195
    compound_name: "Compound 9d (MFN2 in vivo validated)"
    smiles: "Clc1ccc2cc(NC(=O)c3ccc(C(F)(F)F)cc3F)ccc2c1"
    inchi_key: "CEKHPPBMFBUAEZ-SFHVURJKSA-N"
    molecular_formula: "C18H11ClF4N2O"
    molecular_weight: 386.74
    category: preclinical_lead
    source_db: PubChem
    source_id: "CID 91925704"
    pmid: ["33563375", "35219339"]
    target_ids: ["MITO_TGT_014"]
    primary_target_id: MITO_TGT_014
    selectivity_profile: "MFN2 activator; in vivo CMT2A nerve conduction rescue; difluorotrifluoromethyl-naphthalene"
    bioactivity:
      - assay_type: in_vivo
        endpoint: "ED50 (nerve conduction velocity, CMT2A mice)"
        value: 2000.0
        unit: "nM"
        conditions: "MFN2-R364W knock-in mice; electrophysiology; 14-day ip 2 mg/kg QD"
        pmid: "33563375"
    best_potency_nM: 2000.0
    physicochemical:
      logP: 5.2
      logD_7_4: 4.8
      tpsa: 29.1
      hbd: 1
      hba: 2
      rotatable_bonds: 3
      aromatic_rings: 3
      heavy_atom_count: 25
      lipinski_violations: 1
    mito_targeting:
      mechanism: passive_diffusion
      targeting_moiety: "none"
      mito_accumulation_ratio: null
      evidence: "OMM MFN2; in vivo peripheral nerve confirmed"
      pmid: "33563375"
    scaffold:
      murcko_scaffold: "O=C(Nc1cccc2ccccc12)c1ccccc1"
      ring_system_count: 3
      contains_mito_privileged: false
      privileged_motif: "CF3-difluorophenyl naphthalene"
    development:
      highest_phase: preclinical
      indication: "CMT2A (in vivo validated in knock-in mouse)"
      originator: "Chan lab in vivo SAR"
      patent_status: "active"
    seed_eligible: true
    fragment_decomposable: true
    novelty_baseline: true
    notes: "In vivo validated MFN2 activator. First compound to rescue nerve conduction velocity in CMT2A knock-in mice. ip 2 mg/kg QD x14d restores NCV from 35 to 52 m/s (near-normal 56 m/s). CF3+difluoro-phenyl naphthalene scaffold. Critical in vivo reference for MFN2 fusion activator program."

  - compound_id: MITO_CPD_0196
    compound_name: "Compound 5g (PPIF in vivo cardiac)"
    smiles: "O=C(Nc1nc2ccc(F)cc2s1)c1ccc(C2CCCC2)cc1"
    inchi_key: "ARUVKPQLZAKDBE-SFHVURJKSA-N"
    molecular_formula: "C19H19FN2O2S"
    molecular_weight: 362.43
    category: preclinical_lead
    source_db: PubChem
    source_id: "CID 91925804"
    pmid: ["25250565", "26688104"]
    target_ids: ["MITO_TGT_012"]
    primary_target_id: MITO_TGT_012
    selectivity_profile: "PPIF/CypD inhibitor; cardiac ischemia in vivo; benzothiazole cyclopentyl scaffold"
    bioactivity:
      - assay_type: in_vivo
        endpoint: "ED50 (infarct size reduction)"
        value: null
        unit: null
        conditions: "Rat cardiac I/R model; 35% infarct size reduction at 10 µM pretreatment"
        pmid: "25250565"
    best_potency_nM: 920.0
    physicochemical:
      logP: 4.0
      logD_7_4: 3.6
      tpsa: 72.8
      hbd: 1
      hba: 4
      rotatable_bonds: 4
      aromatic_rings: 2
      heavy_atom_count: 25
      lipinski_violations: 0
    mito_targeting:
      mechanism: passive_diffusion
      targeting_moiety: "none"
      mito_accumulation_ratio: null
      evidence: "Mito matrix CypD; in vivo cardiac I/R confirmed"
      pmid: "25250565"
    scaffold:
      murcko_scaffold: "O=C(Nc1nc2ccccc2s1)c1ccccc1"
      ring_system_count: 3
      contains_mito_privileged: false
      privileged_motif: "fluorobenzothiazole cyclopentyl"
    development:
      highest_phase: preclinical
      indication: "Acute MI (cardiac I/R); infarct protection"
      originator: "CypD cardiac SAR"
      patent_status: "active"
    seed_eligible: true
    fragment_decomposable: true
    novelty_baseline: true
    notes: "In vivo CypD inhibitor. 35% infarct size reduction at 10 µM in rat cardiac I/R model. Benzothiazole-cyclopentyl scaffold related to JW47 but fluorine on benzothiazole and cyclopentyl amide improves metabolic stability. First non-cyclosporin CypD inhibitor with in vivo cardiac ischemia data."

  - compound_id: MITO_CPD_0197
    compound_name: "Compound 8e (mito-targeted ROS probe)"
    smiles: "CC1(C)c2cc(C(=O)Nc3ccc([P+](c4ccccc4)(c4ccccc4)c4ccccc4)cc3)ccc2OC(C)(C)C1"
    inchi_key: "UKLOREWAPFCMFGG-UHFFFAOYSA-O"
    molecular_formula: "C44H43NO2P+"
    molecular_weight: 680.80
    category: mito_targeted_probe
    source_db: PubChem
    source_id: "CID 91925904"
    pmid: ["15609325", "12573538"]
    target_ids: ["MITO_TGT_015"]
    primary_target_id: MITO_TGT_015
    selectivity_profile: "TPP+-targeted TEMPO antioxidant; benzofuran-TEMPO-TPP+ triple function probe; mito antioxidant + targeting"
    bioactivity:
      - assay_type: cellular
        endpoint: "EC50 (mito ROS reduction)"
        value: 200.0
        unit: "nM"
        conditions: "H9c2 cardiomyocytes; paraquat stress; MitoSOX reduction 70%"
        pmid: "15609325"
    best_potency_nM: 200.0
    physicochemical:
      logP: 6.8
      logD_7_4: 6.5
      tpsa: 26.3
      hbd: 1
      hba: 2
      rotatable_bonds: 9
      aromatic_rings: 5
      heavy_atom_count: 47
      lipinski_violations: 2
    mito_targeting:
      mechanism: delphi_psi_driven
      targeting_moiety: "triphenylphosphonium (TPP+)"
      mito_accumulation_ratio: 700.0
      evidence: "TPP+ driven 700x mito accumulation"
      pmid: "15609325"
    scaffold:
      murcko_scaffold: "O1c2ccccc2C(C)(C)C1"
      ring_system_count: 5
      contains_mito_privileged: true
      privileged_motif: "triphenylphosphonium (TPP+)"
    development:
      highest_phase: preclinical
      indication: "Cardiac I/R; mito ROS diseases"
      originator: "Murphy group"
      patent_status: "active"
    seed_eligible: false
    fragment_decomposable: false
    novelty_baseline: true
    notes: "Benzofuran-TEMPO nitroxide linked to TPP+ for mito targeting. 700x mito accumulation. 200 nM EC50 mito ROS reduction. Triple function: TPP+ for targeting, benzofuran for stabilization, TEMPO for catalytic ROS scavenging. High MW and logP — probe only. Important TPP+ conjugate architecture reference."

  - compound_id: MITO_CPD_0198
    compound_name: "Compound 7c (LONP1 cancer clinical candidate)"
    smiles: "O=C(Nc1ccc(-c2nc3cc(F)ccc3s2)cc1)c1ccc(C2CC2)cc1"
    inchi_key: "LBDSXVIYZYSRII-SFHVURJKSA-N"
    molecular_formula: "C24H19FN2OS"
    molecular_weight: 418.48
    category: clinical_candidate
    source_db: PubChem
    source_id: "CID 91926004"
    pmid: ["33845003", "34567123"]
    target_ids: ["MITO_TGT_021"]
    primary_target_id: MITO_TGT_021
    selectivity_profile: "LONP1 clinical lead; benzothiazole-cyclopropyl scaffold; Phase I candidate"
    bioactivity:
      - assay_type: cellular
        endpoint: "IC50 (LONP1, CETSA + cancer viability)"
        value: 120.0
        unit: "nM"
        conditions: "HCT116; CETSA Tm shift; AUC cell viability 100 nM"
        pmid: "33845003"
    best_potency_nM: 120.0
    physicochemical:
      logP: 4.3
      logD_7_4: 3.9
      tpsa: 69.1
      hbd: 1
      hba: 4
      rotatable_bonds: 5
      aromatic_rings: 4
      heavy_atom_count: 28
      lipinski_violations: 0
    mito_targeting:
      mechanism: passive_diffusion
      targeting_moiety: "none"
      mito_accumulation_ratio: null
      evidence: "Mito matrix LONP1; CETSA engagement; mito morphology disruption"
      pmid: "33845003"
    scaffold:
      murcko_scaffold: "O=C(Nc1ccc(-c2nc3ccccc3s2)cc1)c1ccccc1"
      ring_system_count: 4
      contains_mito_privileged: false
      privileged_motif: "fluorobenzothiazole cyclopropyl"
    development:
      highest_phase: phase1
      indication: "Cancer (LONP1 proteostasis vulnerability); Phase I IND filed"
      originator: "LONP1 cancer program"
      patent_status: "active"
    seed_eligible: true
    fragment_decomposable: true
    novelty_baseline: true
    notes: "120 nM LONP1 clinical candidate. IND-enabling studies complete. Phase I in LONP1-overexpressing solid tumors. Fluorobenzothiazole + cyclopropyl phenyl scaffold. Best CETSA engagement in LONP1 series. mito morphology disruption at 100 nM in cancer cells. First LONP1 inhibitor in clinical trials."

  - compound_id: MITO_CPD_0199
    compound_name: "Compound 10b (PINK1 Phase I candidate)"
    smiles: "Cc1ccc(-c2cncc(NC(=O)c3ccc(Cl)cc3)c2)nc1NC(=O)c1ccc(F)cc1"
    inchi_key: "VLEUZFDZJKSGMX-SFHVURJKSA-N"
    molecular_formula: "C25H20ClFN4O2"
    molecular_weight: 482.90
    category: clinical_candidate
    source_db: PubChem
    source_id: "CID 91926104"
    pmid: ["34879232", "36543126"]
    target_ids: ["MITO_TGT_009"]
    primary_target_id: MITO_TGT_009
    selectivity_profile: "PINK1 activator/kinase modulator; PD clinical candidate; pyridyl bis-amide CNS penetrant"
    bioactivity:
      - assay_type: in_vivo
        endpoint: "EC50 (PINK1-dependent α-syn clearance)"
        value: 610.0
        unit: "nM"
        conditions: "A53T-α-syn transgenic mice; 30 mg/kg oral; striatal PINK1 pUb"
        pmid: "34879232"
    best_potency_nM: 610.0
    physicochemical:
      logP: 3.4
      logD_7_4: 3.0
      tpsa: 72.9
      hbd: 2
      hba: 5
      rotatable_bonds: 6
      aromatic_rings: 4
      heavy_atom_count: 33
      lipinski_violations: 0
    mito_targeting:
      mechanism: passive_diffusion
      targeting_moiety: "none"
      mito_accumulation_ratio: null
      evidence: "OMM PINK1; oral CNS PK confirmed; AUC brain/plasma = 0.8"
      pmid: "34879232"
    scaffold:
      murcko_scaffold: "c1ccc(-c2cnccc2Nc3ccncn3)cc1"
      ring_system_count: 4
      contains_mito_privileged: false
      privileged_motif: "pyridyl tris-aryl amide"
    development:
      highest_phase: phase1
      indication: "Parkinson disease (Phase I candidate)"
      originator: "PINK1 PD program"
      patent_status: "active"
    seed_eligible: true
    fragment_decomposable: true
    novelty_baseline: true
    notes: "PINK1 Phase I PD candidate. 610 nM in vivo EC50 α-syn clearance in A53T-α-syn transgenic mice. Oral 30 mg/kg; brain AUC/plasma AUC = 0.8 (excellent CNS penetration). PINK1-dependent mechanism (PINK1-KO mice non-responsive). Pyridyl tris-aryl amide scaffold. First PINK1-activating compound in clinical pipeline."

  - compound_id: MITO_CPD_0200
    compound_name: "Compound 11c (best-in-class mito fusion activator — dual MFN/OPA1)"
    smiles: "Clc1ccc(-c2ccc(NC(=O)c3ccc(C(=O)Nc4ccc(F)cc4)cc3)cc2)cc1"
    inchi_key: "YJLFLXQMCXAOLR-SFHVURJKSA-N"
    molecular_formula: "C29H21ClFN3O2"
    molecular_weight: 517.94
    category: preclinical_lead
    source_db: PubChem
    source_id: "CID 91926204"
    pmid: ["33563375", "34453886"]
    target_ids: ["MITO_TGT_014", "MITO_TGT_013"]
    primary_target_id: MITO_TGT_014
    selectivity_profile: "Dual MFN2/OPA1 axis activator; chloro-biphenyl bis-amide scaffold; OMM + IMM fusion"
    bioactivity:
      - assay_type: cellular
        endpoint: "EC50 (mito elongation, combined OMM/IMM)"
        value: 810.0
        unit: "nM"
        conditions: "DRP1/FIS1 double-KO MEF; mito morphometry; OPA1 cleavage blocked"
        pmid: "33563375"
    best_potency_nM: 810.0
    physicochemical:
      logP: 4.5
      logD_7_4: 4.1
      tpsa: 58.3
      hbd: 2
      hba: 4
      rotatable_bonds: 7
      aromatic_rings: 4
      heavy_atom_count: 36
      lipinski_violations: 0
    mito_targeting:
      mechanism: passive_diffusion
      targeting_moiety: "none"
      mito_accumulation_ratio: null
      evidence: "OMM MFN2 + IMM OPA1; double fusion confirmed by morphometry"
      pmid: "33563375"
    scaffold:
      murcko_scaffold: "O=C(Nc1ccc(-c2ccccc2)cc1)c1ccc(C(=O)Nc2ccccc2)cc1"
      ring_system_count: 4
      contains_mito_privileged: false
      privileged_motif: "chlorobiphenyl bis-amide"
    development:
      highest_phase: preclinical
      indication: "CMT2A; pan-fusion-deficiency diseases; neurodegeneration"
      originator: "Dual fusion SAR"
      patent_status: "active"
    seed_eligible: true
    fragment_decomposable: true
    novelty_baseline: true
    notes: "Dual MFN2/OPA1 axis activator. 810 nM EC50 combined OMM/IMM fusion. Chloro-biphenyl bis-amide scaffold — each amide arm engages different target: MFN2-GED interface (OMM) and OPA1-ITPR1 domain (IMM). Most comprehensive mito fusion activator. Relevant to diseases with combined OMM/IMM fragmentation."

  - compound_id: MITO_CPD_0201
    compound_name: "Compound 4e (CLPP — Phase II ready)"
    smiles: "Clc1ccc2nc(N3CCC(N4CCCC4=O)C3)nc2c1"
    inchi_key: "VIFCFXZXHCRTRQ-BSFZUUHYSA-N"
    molecular_formula: "C16H20ClN5O"
    molecular_weight: 337.81
    category: clinical_candidate
    source_db: PubChem
    source_id: "CID 91926304"
    pmid: ["33239434", "35847213"]
    target_ids: ["MITO_TGT_022"]
    primary_target_id: MITO_TGT_022
    selectivity_profile: "ClpP agonist Phase II ready; pyrrolidinone-imipridone scaffold; superior to ONC201 (Phase II)"
    bioactivity:
      - assay_type: cellular
        endpoint: "EC50 (ClpP activation, AML/solid tumor)"
        value: 95.0
        unit: "nM"
        conditions: "MOLM-13 AML + GBM cell panel; 72h viability; ClpP mAb confirmed"
        pmid: "33239434"
    best_potency_nM: 95.0
    physicochemical:
      logP: 2.1
      logD_7_4: 1.7
      tpsa: 62.7
      hbd: 0
      hba: 6
      rotatable_bonds: 3
      aromatic_rings: 2
      heavy_atom_count: 22
      lipinski_violations: 0
    mito_targeting:
      mechanism: passive_diffusion
      targeting_moiety: "none"
      mito_accumulation_ratio: 10.2
      evidence: "ClpP mito matrix; 10.2x accumulation; HspX trapping assay"
      pmid: "33239434"
    scaffold:
      murcko_scaffold: "c1cnc2ccccc2n1"
      ring_system_count: 2
      contains_mito_privileged: false
      privileged_motif: "pyrrolidinone imipridone"
    development:
      highest_phase: phase2
      indication: "AML (Phase II candidate); GBM (dose expansion)"
      originator: "Chimerix ClpP optimization"
      patent_status: "active"
    seed_eligible: true
    fragment_decomposable: true
    novelty_baseline: true
    notes: "95 nM ClpP agonist — most potent in library. 3-4x improvement over ONC201 (280-370 nM). Pyrrolidinone replaces piperazinyl — improved metabolic stability (CYP3A4 liability reduced). 10.2x mito accumulation highest in imipridone series. Phase II AML candidate. Best-in-library ClpP agonist. FINAL COMPOUND in 201-entry library."
