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Mitochondria QSARs Involving Chemical Effects

Mitochondria QSARs Involving Chemical Effects. by Albert Leo Pomona College Medicinal Chemistry Project (1969-1993) BioByte Corp. (1993-present). The Role of Mitochondria in Pharmacotoxicology.

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Mitochondria QSARs Involving Chemical Effects

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  1. MitochondriaQSARs Involving Chemical Effects by Albert Leo Pomona College Medicinal Chemistry Project (1969-1993) BioByte Corp. (1993-present)

  2. The Role of Mitochondria in Pharmacotoxicology • “The role of mitochondria in pharmacotoxicology: a reevaluation of an old, newly emerging topic” (R. Scatena, et al, Am. J. Physiol. Cell Physiol, 293, C12-C21, 2007) points out: • Some antiviral nucleoside analogs display mitochondrial toxicity by inhibiting DNA polymerase-γ. • The more hydrophobic NSAIDs act as UOP. • Some mitochondrial toxicity of drugs depends upon free radical production.

  3. Mitochondria in QSAR • 149 equations dealing with mitochondria • 1290 unique chemical structures • Available as a SMILES file on www.biobyte.com • 26 equations containing 6-X-2,4-dinitro-phenols

  4. Beginnings of Cellular Life • In Beginnings of Cellular Life, Harold Morowitz (Yale University Press, 1992) says: “spontaneous formation of closed membrane vesicles was the initiating event in cellular evolution.” • They maintain separate stable phases in an aqueous environment. • They maintain different chemical compositions between intra- and extra-cellular compartments. • They maintain substantial trans-bilayer electrical voltages, pH differences, and oxidation potentials.

  5. Precursors of Chloroplasts & Mitochondria

  6. Mitochondria Chloroplasts • The result of Intelligent Design, says Michael Behe (?)Are we intelligent enough to refrain from injuring them?

  7. Mitochondrial Function Protonophore: weak acid and hydrophobic (log P > 4) Both ion and neutral forms in innter membrane.

  8. Di-Aryl Amines as Non-Classical Uncouplers Fluazinam - anti-fungal • Set 2447:log 1/C = 0.18 pKa – 1.57 bilin(pKa) + 0.65 log P’ + 4.67; n = 22; r2 = 0.96; OpKa = 6.96

  9. In most cases another (Y) group also present, and so 'buttressing" effect possible. • McGowan volume and/or CMR may help explain the difference.

  10. 2,4-DNP, 6-t-Bu pKa 4.80; logP 3.55 Pentachlorophenol pKa 4.69; logP 5.12 Classical Uncouplers(Protonophores) • Set 599: I-50 respiration, rat liver mitochondriaLog 1/C = 1.73 CLOGP – 1.51 bilinCLOGP -0.51;n = 21; r2 = 0.89; OLP =~5.6

  11. Set 2257:1/C = -0.46 pKa + 2.07 P-F + 0.76 P-P + 0.07 NVE + 12.2; n = 39; r2 = 0.96 Malonoben (SF-6847) insecticide

  12. R = CH3 = BHT R = P+(Ph)3 = Mito-BHT (ant-obesity lead) 2,4-DNP (1930s) Uncouplers in Treatment of Obesity • Binds to adenine nucleotide translocase • Lowers membrane potential (ΔΨm)

  13. Fenfluramine N-Nitroso analog metabolism • Mitochondrial toxicity: membrane swelling and release of Cyt-C.

  14. Kebuzone - anti-rheumatic Pharmaceuticals with UOP action Amiodarone - anti-arrhythmic Protonated logD ~ 5.0; inhibits complexes 1 & II

  15. Complex I-II Inhibitors Capsaicin Analogs • Set 6878:log 1/C = 3.44 CLOGP – 0.28 (CLOGP)2 – 4.67n = 6; r2 = 0.98; OLP = 6.08

  16. Complex I-II Inhibitors Rotenone & Annonacin Analogs • Set 10754:Log 1/C = 0.14 CLOGP + 7.7; n = 5; r2 = 0.93

  17. Complex I-II Inhibitors 4,7-subs. Acridones • Set 2373:Log 1/C = 0.74 CLOGP – 1.53 CLOGP2 – 1.36 σ4 + 3.36; n = 22; r2 = 0.90; OLP = 4.5

  18. Set 3877:Log 1/C = 0.67 CLOGP – 0.93 BiLin CLOGP - 0.35 I-Me + 1.51; n = 13; r2 = 0.86; OLP = 5.6 2,3-alkyl-Quinolones • Set 3876:log P = 0.73 CLOGP – 1.55 BiLinCLOGP + 1.16 I-3Me + 2.69; n = 12; r2 = 0.96; OLP = 5.65

  19. INHIBITORS OF COMPLEX II (Succinic Dehydrogenase) • Prototype:  3-nitropropionic acid (3-NP):O2N-CH2-CH2-CO2H • A natural phytoalexin; present in loco weed (Astragalus); animal toxin. • Human toxin in fungal-contaminated sugar cane (China) • Used as neurotoxin model for Huntington's disease

  20. Complex II-III Inhibition • Set 611: inhibition of succinate dehydrogenase in cinerea botrytis moldLog 1/C = 0.58 CLOGP + 0.043 NVE – 0.219; n = 21; r2 = .88 • Set 699: acting as fungicide on rice sheath blightLog 1/C = -19.9 MgVol + 5.3 MgVol2 + 21.7; n = 24; r2 = 0.88;Opt.vol. = 1.9

  21. Complex II-III Inhibition • Set 1557: Benzanilides as fungicides inhibiting Complex IILog 1/C = 1.04 CLOGP – 1.7 Bilin CLOGP -1.48 Es-X2 – B1-R2 -1.17 σR + 1.33; n = 32; r2 = 0.89; OLP = 5.28

  22. Complex II-III Inhibition • Set 1720: Thiazole-anilides as fungicidesLog 1/C = 0.64 CLOGP + 0.95 σ + 1.2 I 2,6 + 3.89; n = 42; r2 = 0.85 • I2,6 shows that di-ortho substitution is especially strong

  23. Complex II-III Inhibition • Set 2425: Carboxins inhibiting Complex II of yeast pathogen c. laurentiiLog 1/C = -1.95 B1-4 – 0.72 σ – 1.32 I2,6 + 7.9; n = 14; r2 = 087 • In this set, 2,6-disubstitution weakens inhibitory action.

  24. Complex IV Inhibition • Set 1006: Inhibition of cytochrome-C from horse heart mitochondria by alkanols (including -diols)Log 1/C = 0.35 log P – 0.70; n = 7; r2 = 0.91 • Set 1643: Inhibition of cytochrome-C by catechols (from same source)Log 1/C = -5.83 σ + 2.80; n = 9; r2 = 0.97

  25. Complex IV Inhibition • Set 3882: 4-quinolone analogs inhibiting bacterial cytochrome-CLog 1/C = 0.73 CLOGP – 0.83 bilinCLOGP + 0.53n = 12; r2 = 0.95; OLP = 5.86 • Set 4985: Very similar relationships with cytochrome-C from beef heart mitochondriaLog 1/C = 0.86 CLOGP – 1.29 bilinCLOGP + 2.82n = 21; r2 = 0.90; OLP = 6.35

  26. Set 7095: C for maximal respiration release in rat liver mitochondrialog 1/C = -1.33 σ - + 9.71; n = 5; r2 = 0.96 • Set 7096: C for inhibition of ATP synthesis in rat liver mitochondrialog 1/C = -1.26 σ -- + 9.56; n = 6; r2 = 0.90 anilino-thiadiazoles Inhibitors of mammary sarcomas

  27. Mitochondrial Function Protonophore: weak acid and hydrophobic (log P > 4) Both ion and neutral forms in innter membrane.

  28. Chloroplast ATP Production

  29. Triazine inhibitors of Plastoquinone • Set 2252:Log 1/C = 0.61 log P -0.96 bilinLogP -0.24 WRB-X -0.2 D-Y -0.51 T1-Y -2.8 I-Me + 8.46;n = 47; r2 = 0.89; OLP = 4.5

  30. Ubiquinone CoQ in mitochondria Plastoquinone (atrazine target) in chloroplasts

  31. Complex V Inhibition • Set 8510: Salicylanilides on exchange of P with ATP in fly mitochondriaLog 1/C = 0.056 NVE + 1.00; n = 15; r2 = 0.95

  32. Complex V Inhibition • Set 9574: N,N’-diphenyl thiorureas inducing maximal release of state and respiration in rat liver mitochondriaLog 1/C = 1.91 σY = 0.54 L-X + 2.45; n = 12; r2 = 0.95

  33. Anilino-Thiadiazoles • Set 116: Rat liver mitochondria; 2-X-anilino-1,3,4-thiadiazoles; uncoupling oxidative phosphorylationLog 1/C = 1.01 I(CF3) -2.13 σ + 8.83; n = 11; r2 = 0.89 • Set 117: Spinach chloroplasts; 2-X-anilino-1,3,4-thiadiazoles; uncoupling photo-phosphorylationLog 1/C = 1.87 I(CF3) + 0.43 σ - + 3.5; n = 13; r2 = 0.9

  34. Pendimethalin(UOP measured; contradicts 1999 EPA manual) Trifluralin(UOP measured in plant mitochondria) Uncouplers in Both Mitochondria & Chloroplasts Oryzalin (probable)

  35. Measurement of Proton Gradient (ΔΨm) • Now available as a simple kit; e.g. Molecular Probes B-34,950, Mitotracker • Why not used during drug and pesticide development? Basis for QSARs? • MTT Assay for mitochondrial reductase: could it be basis for QSAR?

  36. Acknowledgements • Dr. Gilman Veith: for his support, both moral and financial. • Prof. Corwin Hansch: for his skill and persistence in accumulating and organizing the data for so many QSARs. • Prof. Toshio Fujita: for his insight in creating and applying QSARs. • Mr. Michael Medlin: for preparing the slides for this presentation.

  37. Consequence of Mitochondrial Dysfunction • Production of ROS (e.g. H2O2) from non-phosphorylating respiration results in oxidative stress. • Disability of aging most commonly ascribed to this oxidative stress  • mDNA not as well protected nor as easily repaired as nDNA • Mit.-dysfunction signaled to nucleus via RR (retrograde response) but this fails thru extensive use. • In simpler life forms (yeast, C.elegans) a deficiency in complex IV (cytochrome-c) lengthens life span, but "quality of life" not a concern. • Could be a major factor in degenerative diseases:  Parkinson's, Alzheimer's, neuropathy, myopathy, Type II Diabetes. etc.

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