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QSAR features for inhibitors of mitochondrial bioenergetics.

QSAR features for inhibitors of mitochondrial bioenergetics. Anatoly A. Starkov. e. SDH. Oxygen. NADH. , CoQH 2. C-IV. C-III. e. e. e. e. e. e. e. C-I. C. FMN. Electron transfer in the respiratory chain. H +. p.m.f. = DY + D pH. H +. H +. IM. CoQ. CoQ. Oxygen.

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QSAR features for inhibitors of mitochondrial bioenergetics.

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  1. QSAR features for inhibitors of mitochondrial bioenergetics. Anatoly A. Starkov

  2. e SDH Oxygen NADH , CoQH2 C-IV C-III e e e e e e e C-I C FMN Electron transfer in the respiratory chain H+ p.m.f. = DY + DpH H+ H+ IM CoQ CoQ Oxygen Water Fumarate Succinate Fuel Supply System NAD+ NADH

  3. A. UNCOUPLING. • What is “uncoupling”? • What are “uncouplers”? • What are the mechanisms of uncoupling? • How much uncoupling is toxic? • Is a class-independent QSAR model for uncouplers possible? What descriptors should be selected? • What models should be used to test the uncouplers?

  4. Classical definitions: • Uncoupling of oxidative phosphorylation is a process de-coupling oxygen consumption from ATP production. • Uncouplers: • Stimulate resting respiration. • Decrease ATP yield (P:O ratio). • Activate latent ATPase.

  5. UNCOUPLING:. any energy-dissipating process competing for energy with routine mitochondrial functions, thus inducing a metabolically futile wasting of energy. Wallace KB, Starkov AA. Mitochondrial targets of drug toxicity. Annu Rev Pharmacol Toxicol. 2000;40:353-88.

  6. Proton shuttling by lipophilic weak acids. 1. 2. HA2- A- H+ H+ H+ H+ A- AH A- AH + + AH Respiratory chain Respiratory chain IM IM Matrix Matrix AH - - A- A- AH AH DY DY H+ H+ H+ H+ DpH DpH substituted phenols trifluoromethylbenzimidazoles salicylanilides carbonylcyanide phenylhydrazones

  7. Blaikie FH, Brown SE, Samuelsson LM, Brand MD, Smith RA, Murphy MP. Targeting dinitrophenol to mitochondria: limitations to the development of a self-limiting mitochondrial protonophore. Biosci Rep. 2006 Jun;26(3):231-43.

  8. Terada H. Uncouplers of oxidative phosphorylation. Environ Health Perspect. 1990 Jul;87:213-8.

  9. [Uncoupler] max State 3 respiration rate State 4, nmol O2/min/mg [uncoupler], mM

  10. Proton shuttling by lipophilic weak bases and ion pairs. 4. 3. H+ H+ H+ H+ RN RN+ RN RNA-H+ + + A- Respiratory chain Respiratory chain IM IM Matrix Matrix A- - - RN RN RN+ RNA-H+ DY DY H+ H+ H+ H+ DpH DpH amine local anesthetics

  11. Protein –mediated uncoupling by non-permeating anions and protein modifying reagents. 6. 5. H+ H+ H+ H+ AH A- + + Respiratory chain P Respiratory chain P IM IM Matrix Matrix - - A- AH DY DY DpH DpH H+ H+ H+ H+ P: ATP/ADP translocator, Glutamate transporter P: Uncoupling Protein 1 (UCP1), anion carriers, membrane-active peptides, Permeability transition Pore (mPTP). Long-chain fatty acids, SDS, 2,4-DNP Long-chain fatty acids, SH-modifying reagents.

  12. Ion cycling. 7. 2H+ H+ Ca2+ + Respiratory chain U E IM Matrix - Ca2+ DY 2H+ H+ DpH U: Ca2+ uniporter. E: Ca2+ ionophores. (Variant : U=valinomycin, Ca2+ =K+, E=nigericine)

  13. 8. Uncoupling due to the permeability transition pore (mPTP). 1. Normal Ca2+ signaling: ER storage Ca2+ signal Cytosol 2H+ H+ Ca2+ Ca2+ PTP U RC E IM DpH DY Ca2+ Ca2+ + 2H+ H+ + + CypD + precipitate Fuel Supply System Matrix

  14. 2. Pathological Ca2+ flooding opens mPTP: ER storage Ca2+ flooding Cytosol 2H+ H+ Ca2+ Ca2+ PTP U RC E IM DpH DY Ca2+ Ca2+ + 2H+ H+ + + CypD + precipitate Fuel Supply System Matrix

  15. Classical efficient uncoupler: 4<pKa<7.2, 3<logP<8 McLaughlin SG, Dilger JP. Transport of protons across membranes by weak acids. Physiol Rev. 1980 Jul;60(3):825-63.

  16. McLaughlin SG, Dilger JP. Transport of protons across membranes by weak acids. Physiol Rev. 1980 Jul;60(3):825-63.

  17. Minimum reasonable set of parameters to consider: Classical: 4<pKa<7.2, 3<logP<8 Information on the surrounding: pH out and in, lipid phase volume, lipid phase(s) dielectric constants and viscosity, gradient of the electrical membrane potential across the membrane, total amount of a compound.

  18. Spycher S, Smejtek P, Netzeva TI, Escher BI. Toward a class-independent quantitative structure--activity relationship model for uncouplers of oxidative phosphorylation. Chem Res Toxicol. 2008 Apr;21(4):911-27.

  19. Spycher S, Smejtek P, Netzeva TI, Escher BI. Toward a class-independent quantitative structure--activity relationship model for uncouplers of oxidative phosphorylation. Chem Res Toxicol. 2008 Apr;21(4):911-27.

  20. Black lipid membranes as a model to test the intrinsic efficiency of uncouplers: McLaughlin SG, Dilger JP. Transport of protons across membranes by weak acids. Physiol Rev. 1980 Jul;60(3):825-63.

  21. Isolated mammalian mitochondria as a model to test the toxicity of uncouplers Ilivicky J, Casida JE. Uncoupling action of 2,4-dinitrophenols, 2-trifluoromethylbenzimidazoles and certain other pesticide chemicals upon mitochondria from different sources and its relation to toxicity. Biochem Pharmacol. 1969 Jun;18(6):1389-401.

  22. B. Inhibitors of the respiratory chain complexes. • What do they do? – inhibit electron transport thereby suppressing DmH+ generation and stimulating ROS production. • How many are known? – a few hundreds of natural compounds and a gazillion of synthetic chemicals. • Are there some common chemical features in these compounds? – yes and no. • Is their MOA similar? – yes and no. • Is a class-independent QSAR model for the RC inhibitors possible? – Perhaps, but not there yet. • Why it is so? – insufficient knowledge of RC complexes and their structural diversity. • What models should be used to test the RC inhibitors? – isolated mammalian mitochondria.

  23. SDH C-IV C-III e e e e e e e C-I C FMN ROS ROS ROS ROS ROS IM CoQ CoQ Oxygen Water Fumarate Succinate Fuel Supply System NAD+ NADH

  24. e e e e e e Qo Qi CoQ:Cytochrome c reductase (RC Complex III) ISP Stigmatellin Cyt.c1 Qo site Cyt.c +DY QH2 Myxothiazol IM blow Q QH2 bhigh A Qi site Matrix side Antimycin -DY

  25. Classical inhibitors of CoQ:Cytochrome c reductase (RC Complex III) Antimycin A Myxothiazol Stigmatellin

  26. Complexity of mammalian NADH:CoQ reductase (RC Complex I) N6a N6b N2 N1b N4 N5 N7 N1a N3 FMN

  27. PSST subunit of Complex I is a common target for many and various inhibitors. Inhibitor binding site Schuler F, Casida JE. The insecticide target in the PSST subunit of complex I. Pest Manag Sci. 2001 Oct;57(10):932-40

  28. Different classes of the Q site Complex I inhibitors. Degli Esposti M. Inhibitors of NADH-ubiquinone reductase: an overview. Biochim Biophys Acta. 1998 May 6;1364(2):222-35.

  29. Future developments toward QSAR model of mitochondrial poisons: 1. Create a realistic biophysical model of the inner mitochondrial membrane; 2. Obtain more detailed information on the molecular structure of mitochondrial proteins targeted by toxins; 3. Create a unified database of mitochondrial toxins and analyze it toward both their molecular properties and the mechanisms of intrinsic activity; 4. Create a good team of researchers with proper expertise (and funding) to develop and validate QSAR models in a relevant biological model (isolated mitochondria) under physiologically meaningful conditions.

  30. [ATP] 100 nmol ATP DY (~20 mV) ADP State 4’ 1 min [O2]=0 DY Mito State 3 O2 consumed ADP ADP State 4 ADP V state 3 50 nmol O2 V state 4,4’ 1 min ADP:O Coupled respiration [O2]=0

  31. V(u) state 3 V(u) state 4,4’ ADP:O(u) Uncoupled respiration 2,4-DNP [ATP] ADP 100 nmol ATP DY (~20 mV) 1 min Mito [O2]=0 O2 consumed DY ADP 2,4-DNP ADP 50 nmol O2 1 min [O2]=0

  32. V(u) state 3 V state 3 V(u) state 4,4’ V state 4,4’ ADP:O(u) ADP:O Coupled Uncoupled = < > less ATP for the same O2 and substrates Uncoupling:

  33. Ilivicky J, Casida JE. Uncoupling action of 2,4-dinitrophenols, 2-trifluoromethylbenzimidazoles and certain other pesticide chemicals upon mitochondria from different sources and its relation to toxicity. Biochem Pharmacol. 1969 Jun;18(6):1389-401.

  34. H2O2 emission, % of max H2O2 emission, pmol/min/mg ROS production is regulated by DY

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