Computational models for predicting interactions with cytochrome p450 enzyme

Current Topics in Medicinal Chemistry

Volumn 6, Issue 15, 2006, Pages 1609-1618

  Arimoto, Rieko ^a  

^a VERTEX PHARMACEUTICALS   (United States)

Author keywords

3D QSAR; CYP1A subfamily; Neural network; Pharmacophore modeling; Support vector machine (SVM)

Indexed keywords

ANALGESIC AGENT; ANTIARRHYTHMIC AGENT; BETA ADRENERGIC RECEPTOR BLOCKING AGENT; CLOZAPINE; COUMARIN DERIVATIVE; CYTOCHROME P450 1A2; CYTOCHROME P450 2A6; CYTOCHROME P450 2C9; CYTOCHROME P450 3A4; DIAZEPAM; FLAVANOID; IMIPRAMINE; ISOENZYME; LACTONE DERIVATIVE; METHOXSALEN; MEXILETINE; MIDAZOLAM; NAPHTHALENE DERIVATIVE; NAPROXEN; PHENPROCOUMON; QUINOLINE DERIVATIVE; QUINOLONE DERIVATIVE; RILUZOLE; SULFAPHENAZOLE; THEOPHYLLINE; TRANYLCYPROMINE; TRICYCLIC ANTIDEPRESSANT AGENT; UNINDEXED DRUG; URICOSURIC AGENT; WARFARIN;

ANALYTIC METHOD; CHEMICAL STRUCTURE; DRUG BINDING SITE; DRUG CLEARANCE; DRUG DESIGN; DRUG METABOLISM; DRUG SYNTHESIS; ENZYME INHIBITION; ENZYME METABOLISM; ENZYME SPECIFICITY; HUMAN; MATHEMATICAL COMPUTING; NONHUMAN; PHARMACOPHORE; PREDICTION; PROTEIN INTERACTION; QUANTITATIVE STRUCTURE ACTIVITY RELATION; REVIEW; STATISTICAL MODEL; STRUCTURAL HOMOLOGY; XENOBIOTIC METABOLISM;

COMPUTATIONAL BIOLOGY; COMPUTER SIMULATION; CYTOCHROME P-450 ENZYME SYSTEM; ENZYME INHIBITORS; HUMANS; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 33748105936     PISSN: 15680266     EISSN: None     Source Type: Journal    
DOI: 10.2174/156802606778108951     Document Type: Review

References (104)

1. Lichter, J. B.; Kurth, J. H. The impact of pharmacogenetics on the future of healthcare. Curr. Opin. Biotechnol. 1997, 8, 692-695.
2. Honig, P. K.; Wortham D. C.; Zamani, K.; Conner, D. P.; Mullin, J. C.; Cantilena, L. R. Terfenadine-ketoconazole interaction. Pharmacokinetic and electrocardiographic consequences. JAMA 1993, 269, 1513-1518.
3. Krayenbuhl, J. C.; Vozeh, S.; Kondo-Oestreicher, M.; Dayer, P. Drug-drug interactions of new active substances: mibefradil example. Eur. J. Clin. Pharmacol. 1999, 55, 559-565.
4. Ahmad, S.; Wolfe, S. Cisapride and torsades de pointes. The Lancet 1995, 345, 508.
5. Boxenbaum, H. Cytochrome P450 3A4 in vivo ketoconazole competitive inhibition: determination of Ki and dangers associated with high clearance drugs in general. J. Pharm. Pharm. Sci. 1999, 2, 47-52.
6. Lin, J. H.; Lu, A. Y. Inhibition and induction of cytochrome P450 and the clinical implications. Clin. Pharmacokinet. 1998, 35, 361-390.
7. Shimada, T.; Yamazaki, H.; Mimura, M.; Inui, Y.; Guengerich, F. P. Interindividual variations in human liver cytochrome P-450 enzymes involved in the oxidation of drugs, carcinogens and toxic chemicals: studies with liver microsomes of 30 Japanese and 30 Caucasians. J. Pharmacol. Exp. Ther. 1994, 270, 414-423.
8. Ghoneim, M. M.; Korttila, K.; Chiang, C. K.; Jacobs, L.; Schoenwald, R. D.; Mewaldt, S. P.; Kayaba, K. O. Diazepam effects and kinetics in Caucasians and Orientals. Clin. Pharmacol. Ther. 1981, 29, 749-756.
9. Crespi, C. L.; Miller, V. P.; Penman, B. W. High throughput screening for inhibition of cytochrome P450 metabolism. Med. Chem. Res. 1998, 8, 457-471.
10. Crespi, C. L.; Miller, V. P.; Penman, B. W. Microtiter plate assays for inhibition of human, drug-metabolizing cytochromes P450. Anal. Biochem. 1997, 248, 188-190.
11. Cohen, L. H.; Remley, M. J.; Raunig, D.; Vaz, A. D. In vitro drug interactions of cytochrome p450: an evaluation of fluorogenic to conventional substrates. Drug Metab. Dispos. 2003, 31, 1005-1015.
12. Zlokarnik, G.; Grootenhuis, P. D.; Watson, J. B. High throughput P450 inhibition screens in early drug discovery. Drug Discov. Today 2005, 10, 1443-1450.
13. de Groot, M. J.; Ekins, S. Pharmacophore modeling of cytochromes P450. Adv. Drug Deliv. Rev. 2002, 54, 367-383.
14. Ekins, S.; de Groot, M. J.; Jones, J. P. Pharmacophore and three-dimensional quantitative structure activity relationship methods for modeling cytochrome p450 active sites. Drug Metab Dispos 2001, 29, 936-944.
15. de Graaf, C.; Vermeulen, N. P.; Feenstra, K. A. Cytochrome p450 in silico: an integrative modeling approach. J. Med. Chem. 2005, 48, 2725-2755.
16. Jalaie, M.; Arimoto, R.; Gifford, E.; Schefzick, S.; Waller, C. L. Prediction of drug-like molecular properties: modeling cytochrome P450 interactions. Methods Mol. Biol. 2004, 275, 449-520.
17. Williams, P. A.; Cosme, J.; Ward, A.; Angove, H. C.; Matak Vinkovic, D.; Jhoti, H. Crystal structure of human cytochrome P450 2C9 with bound warfarin. Nature 2003, 424, 464-468.
18. Wester, M. R.; Yano, J. K.; Schoch, G. A.; Yang, C.; Griffin, K. J.; Stout, C. D.; Johnson, E. F. The structure of human microsomal cytochrome P450 2C9 complexed with flurbiprofen at 2.0 A resolution. J. Biol. Chem. 2004, 279, 35630-35637.
19. Williams, P. A.; Cosme, J.; Vinkovic, D. M.; Ward, A.; Angove, H. C.; Day, P. J.; Vonrhein, C.; Tickle, I. J.; Jhoti, H. Crystal structures of human cytochrome P450 3A4 bound to metyrapone and progesterone. Science 2004, 305, 683-686.
20. Yano, J. K.; Wester, M. R.; Schoch, G. A.; Griffin, K. J.; Stout, C. D.; Johnson, E. F. The structure of human microsomal cytochrome P450 3A4 determined by X-ray crystallography to 2.05 A resolution. J. Biol. Chem. 2004, 279, 38091-38094.
21. Schoch, G. A.; Yano, J. K.; Wester, M. R.; Griffin, K. J.; Stout, C. D.; Johnson, E. F. Structure of human microsomal cytochrome P450 2C8: Evidence for a peripheral fatty acid binding site. J. Biol. Chem. 2004, 279, 9497-9503.
22. Lewis, D. F.; Ioannides, C.; Parke, D. V. Molecular dimensions of the substrate binding site of cytochrome P-448. Biochem. Pharmacol. 1986, 35, 2179-2185.
23. Sanz, F.; Lopez-de-Brinas, E.; Rodriguez, J.; Manaut, F. Theoretical study on the metabolism of caffeine by cytochrome p450 1A2 and its inhibition. Quant. Struct.-Act. Relat. 1994, 13, 281-284.
24. Fuhr, U.; Strobl, G.; Manaut, F.; Anders, E. M.; Soergel, F.; Lopez de Brinas, E. Quinolone Antibacterial Agents: Relationship between Structure and In Vitro Inhibition of the Human Cytochrome P450 Isoform CYP1A2. Mol. Pharmacol. 1993, 43, 191-199.
25. Lee, H.; Yeom, H.; Kim, Y. G.; Yoon, C. N.; Jin, C.; Choi, J. S.; Kim, B. R.; Kim, D. H. Structure-related inhibition of human hepatic caffeine N3-demethylation by naturally occurring flavonoids. Biochem. Pharmacol. 1998, 55, 1369-1375.
26. Korhonen, L. E.; Rahnasto, M.; Mahonen, N. J.; Wittekindt, C.; Poso, A.; Juvonen, R. O.; Raunio, H. Predictive three-dimensional quantitative structure-activity relationship of cytochrome P450 1A2 inhibitors. J. Med. Chem. 2005, 48, 3808-3815.
27. Cramer, I. I. I. R. D.; Patterson, D. E.; Bunce, J. D. Comparative molecular field analysis (CoMFA). 1. Effect of shape on binding of steroids to carrier proteins. J. Am. Chem. Soc. 1988, 110, 5959-5967.
28. Goodford, P. J. A computational procedure for determining energetically favorable binding sites on biologically important macromolecules. J. Med. Chem. 1985, 28, 849-857.
29. Choban, K. K.; Paine, S. W.; Mistry, J.; Barton, P.; Davis, A. M. A rapid computational filter for cytochrome P450 1A2 inhibition potential of compound libraries. J. Med. Chem. 2005, 48, 5154-5161.
30. Breiman, L. Classification and regression trees; Wadsworth: Belmont, CA, 1984.
31. Yano, J. K.; Hsu, M. H.; Griffin, K. J.; Stout, C. D.; Johnson, E. F. Structures of human microsomal cytochrome P450 2A6 complexed with coumarin and methoxsalen. Nat. Struct. Mol. Biol. 2005, 12, 822-823.
32. Asikainen, A.; Tarhanen, J.; Poso, A.; Pasanen, M.; Albava, E.; Juvonen, R. O. Predictive value of comparative molecular field analysis modelling of naphthalene inhibition of human CYP2A6 and mouse CYP2A5 enzymes. Toxicol. In Vitro 2003, 17, 449-455.
33. Poso, A.; Gynther, J.; Juvonen, R. A comparative molecular field analysis of cytochrome P450 2A5 and 2A6 inhibitors. J. Comput. Aided Mol. Des. 2001, 15, 195-202.
34. Rahnasto, M.; Raunio, H.; Poso, A.; Wittekindt, C.; Juvonen, R. O. Quantitative structure-activity relationship analysis of inhibitors of the nicotine metabolizing CYP2A6 enzyme. J. Med. Chem. 2005, 48, 440-449.
35. He, M.; Korzekwa, K. R.; Jones, J. P.; Rettie, A. E.; Trager, W. F. Structural forms of phenprocoumon and warfarin that are metabolized at the active site of CYP2C9. Arch. Biochem. Biophys. 1999, 372, 16-28.
36. Jones, B. C.; Hawksworth, G.; Horne, V. A.; Newlands, A.; Morsman, J.; Tute, M. S.; Smith, D. A. Putative active site template model for cytochrome P4502C9 (tolbutamide hydroxylase). Drug Metab. Dispos. 1996, 24, 260-266.
37. Mancy, A.; Broto, P.; Dijols, S.; Dansette, P. M.; Mansuy, D. The substrate binding site of human liver cytochrome P450 2C9: an approach using designed tienilic acid derivatives and molecular modeling. Biochemistry 1995, 34, 10365-10375.
38. Mancy, A.; Dijols, S.; Poli, S.; Guengerich, P.; Mansuy, D. Interaction of sulfaphenazole derivatives with human liver cytochromes P450 2C: molecular origin of the specific inhibitory effects of sulfaphenazole on CYP 2C9 and consequences for the substrate binding site topology of CYP 2C9. Biochemistry 1996, 35, 16205-16212.
39. Poli-Scaife, S.; Attias, R.; Dansette, P. M.; Mansuy, D. The substrate binding site of human liver cytochrome P450 2C9: an NMR study. Biochemistry 1997, 36, 12672-12682.
40. Jones, J. P.; He, M.; Trager, W. F.; Rettie, A. E. Three-dimensional quantitative structure-activity relationship for inhibitors of cytochrome P4502C9. Drug Metab. Dispos. 1996, 24, 1-6.
41. Haining, R. L.; Jones, J. P.; Henne, K. R.; Fisher, M. B.; Koop, D. R.; Trager, W. F.; Rettie, A. E. Enzymatic determinants of the substrate specificity of CYP2C9: role of B'-C loop residues in providing the pi-stacking anchor site for warfarin binding. Biochemistry 1999, 38, 3285-3292.
42. Rao, S.; Aoyama, R.; Schrag, M.; Trager, W. F.; Rettie, A.; Jones, J. P. A refined 3-dimensional QSAR of cytochrome P450 2C9: computational predictions of drug interactions. J. Med. Chem. 2000, 43, 2789-2796.
43. Locuson, C. W.; Wahlstrom, J. L. Three-dimensional quantitative structure-activity relationship analysis of cytochromes p450: effect of incorporating higher-affinity ligands and potential new applications. Drug Metab. Dispos. 2005, 33, 873-878.
44. Ekins, S.; Bravi, G.; Binkley, S.; Gillespie, J. S.; Ring, B. J.; Wikel, J. H.; Wrighton, S. A. Three- and four-dimensional-quantitative structure activity relationship (3D/4D-QSAR) analyses of CYP2C9 inhibitors. Drug Metab. Dispos. 2000, 28, 994-1002.
45. Norinder, U. In silico modelling of ADMET - a minireview of work from 2000 to 2004. SAR QSAR Environ. Res. 2005, 16, 1-11.
46. Williams, P. A.; Cosme, J.; Sridhar, V.; Johnson, E. F.; McRee, D. E. Mammalian microsomal cytochrome P450 monooxygenase: structural adaptations for membrane binding and functional diversity. Mol. Cell 2000, 5, 121-131.
47. De Groot, M. J.; Alex, A. A.; Jones, B. C. Development of a combined protein and pharmacophore model for cytochrome P450 2C9. J. Med. Chem. 2002, 45, 1983-1993.
48. Afzelius, L.; Zamora, I.; Ridderstrom, M.; Andersson, T. B.; Karlen, A.; Masimirembwa, C. M. Competitive CYP2C9 inhibitors: enzyme inhibition studies, protein homology modeling, and three-dimensional quantitative structure-activity relationship analysis. Mol. Pharmacol. 2001, 59, 909-919.
49. Afzelius, L.; Masimirembwa, C. M.; Karlen, A.; Anderson, T. B.; Zamora, I. Discriminant and quantitative PLS analysis of competitive CYP2C9 inhibitors versus non-inhibitors using alignment independent GRIND descriptors. J. Comput. Aided Mol. Des. 2002, 16, 443-458.
50. Pastor, M.; Cruciani, G.; McLay, I.; Pickett, S.; Clementi, S. GRid-INdependent descriptors (GRIND): a novel class of alignment-independent three-dimensional molecular descriptors. J. Med. Chem. 2000, 43, 3233-3243.
51. Afzelius, L.; Zamora, I.; Masimirembwa, C. M.; Karlen, A.; Andersson, T. B.; Mecucci, S.; Baroni, M.; Cruciani, G. Conformer- and Alignment-Independent Model for Predicting Structurally Diverse Competitive CYP2C9 Inhibitors. J. Med. Chem. 2004, 47, 907-914.
52. Melet, A.; Assrir, N.; Jean, P.; Pilar Lopez-Garcia, M.; Marques-Soares, C.; Jaouen, M.; Dansette, P. M.; Sari, M. A.; Mansuy, D. Substrate selectivity of human cytochrome P450 2C9: importance of residues 476, 365, and 114 in recognition of diclofenac and sulfaphenazole and in mechanism-based inactivation by tienilic acid. Arch. Biochem. Biophys. 2003, 409, 80-91.
53. Wolff, T.; Distlerath, L. M.; Worthington, M. T.; Groopman, J. D.; Hammons, G. J.; Kadlubar, F. F.; Prough, R. A.; Martin, M. V.; Guengerich, F. P. Substrate specificity of human liver cytochrome P-450 debrisoquine 4-hydroxylase probed using immunochemical inhibition and chemical modeling. Cancer Res. 1985, 45, 2116-2122.
54. Meyer, U. A.; Gut, J.; Kronbach, T.; Skoda, C.; Meier, U. T.; Catin, T.; Dayer, P. The molecular mechanisms of two common polymorphisms of drug oxidation-evidence for functional changes in cytochrome P-450 isozymes catalysing bufuralol and mephenytoin oxidation. Xenobiotica 1986, 16, 449-464.
55. Koymans, L.; Vermeulen, N. P.; van Acker, S. A.; te Koppele, J. M.; Heykants, J. J.; Lavrijsen, K.; Meuldermans, W.; Donne-Op den Kelder, G. M. A predictive model for substrates of cytochrome P450-debrisoquine (2D6). Chem. Res. Toxicol. 1992, 5, 211-219.
56. de Groot, M. J.; Bijloo, G. J.; Hansen, K. T.; Vermeulen, N. P. Computer prediction and experimental validation of cytochrome P4502D6-dependent oxidation of GBR 12909. Drug Metab. Dispos. 1995, 23, 667-669.
57. de Groot, M. J.; Vermeulen, N. P.; Kramer, J. D.; van Acker, F. A.; Donne-Op den Kelder, G. M. A three-dimensional protein model for human cytochrome P450 2D6 based on the crystal structures of P450 101, P450 102, and P450 108. Chem. Res. Toxicol. 1996, 9, 1079-1091.
58. Ellis, S. W.; Hayhurst, G. P.; Smith, G.; Lightfoot, T.; Wong, M. M.; Simula, A. P.; Ackland, M. J.; Steinberg, M. J.; Leonard, M. S.; Tucker, G. T.; Wolf, C. R. Evidence that aspartic acid 301 is a critical substrate-contact residue in the active site of cytochrome P450 2D6. J. Biol. Chem. 1995, 270, 29055-29058.
59. de Groot, M. J.; Bijloo, G. J.; Martens, B. J.; van Acker, F. A.; Vermeulen, N. P. A refined substrate model for human cytochrome P450 2D6. Chem. Res. Toxicol. 1997, 10, 41-48.
60. de Groot, M. J.; Bijloo, G. J.; van Acker, F. A.; Fonseca Guerra, C.; Snijders, J. G.; Vermeulen, N. P. Extension of a predictive substrate model for human cytochrome P4502D6. Xenobiotica 1997, 27, 357-368.
61. Onderwater, R. C.; Venhorst, J.; Commandeur, J. N.; Vermeulen, N. P. Design, synthesis, and characterization of 7-methoxy-4-(aminomethyl)coumarin as a novel and selective cytochrome P450 2D6 substrate suitable for high-throughput screening. Chem. Res. Toxicol. 1999, 12, 555-559.
62. de Groot, M. J.; Ackland, M. J.; Home, V. A.; Alex, A. A.; Jones, B. C. Novel approach to predicting P450-mediated drug metabolism: development of a combined protein and pharmacophore model for CYP2D6. J. Med. Chem. 1999, 42, 1515-1524.
63. Hayhurst, G. P.; Harlow, J.; Chowdry, J.; Gross, E.; Hilton, E.; Leonard, M. S.; Tucker, G. T.; Ellis, S. W. Influence of phenylalanine-481 substitutions on the catalytic activity of cytochrome P450 2D6. Biochem. J. 2001, 355, 373-379.
64. de Groot, M. J.; Ackland, M. J.; Horne, V. A.; Alex, A. A.; Jones, B. C. A novel approach to predicting P450 mediated drug metabolism CYP2D6 catalyzed N-dealkylation reactions and qualitative metabolite predictions using a combined protein and pharmacophore model for CYP2D6. J. Med. Chem. 1999, 42, 4062-4070.
65. Haji-Momenian, S.; Rieger, J. M.; Macdonald, T. L.; Brown, M. L. Comparative molecular field analysis and QSAR on substrates binding to cytochrome p450 2D6. Bioorg. Med. Chem. 2003, 11, 5545-5554.
66. Strobl, G. R.; Von Kruedener, S.; Stockigt, J.; Guengerich, F. P.; Wolff, T. Development of a pharmacophore for inhibition of human liver cytochrome P- 450 2D6: Molecular modeling and inhibition studies. J. Med. Chem. 1993, 36, 1136-1145.
67. Ekins, S.; Bravi, G.; Binkley, G.; Binkley, S.; Gillespie, J. S.; Ring, B. J.; Wikel, J. H.; Wrighton, S. A. Three and four dimensional-quantitative structure activity relationship (3D/4D-QSAR) analyses of CYP2DP inhibitors. Pharmacogenetics 1999, 9, 477-489.
68. Klebe, G. Comparative molecular similarity indices analysis: CoMSIA. Perspect Drug Discovery Des. 1998, 12-14, 87-104.
69. Vaz, R. J.; Nayeem, A.; Santone, K.; Chandrasena, G.; Gavai, A. V. A 3D-QSAR model for CYP2D6 inhibition in the aryloxypropanolamine series. Bioorg. Med. Chem. Lett. 2005, 15, 3816-3820.
70. Le Bourdonnec, B.; Ajello, C. W.; Seida, P. R.; Susnow, R. G.; Cassel, J. A.; Belanger, S.; Stabley, G. J.; DeHaven, R. N.; DeHaven-Hudkins, D. L.; Dolle, R. E. Arylacetamide kappa opioid receptor agonists with reduced cytochrome P450 2D6 inhibitory activity. Bioorg. Chem. Lett. 2005, 15, 2647-2652.
71. Guengerich, F. P.; Miller, G. P.; Hanna, I. H.; Martin, M. V.; Leger, S.; Black, C.; Chauret, N.; Silva, J. M.; Trimble, L. A.; Yergey, J. A.; Nicoll-Griffith, D. A. Diversity in the oxidation of substrates by cytochrome P450 2D6: Lack of an obligatory role of aspartate 301-substrate electrostatic bonding. Biochemistry 2002, 41, 11025-11034.
72. Wrighton, S. A.; Schuetz, E. G.; Thummel, K. E.; Shen, D. D.; Korzekwa, K. R.; Watkins, P. B. The human CYP3A subfamily: practical considerations. Drug. Metab. Rev. 2000, 32, 339-361.
73. Hutzler, J. M.; Tracy, T. S. Atypical kinetic profiles in drug metabolism reactions. Drug Metab. Dispos. 2002, 30, 355-362.
74. Korzekwa, K. R.; Krishnamachary, N.; Shou, M.; Ogai, A.; Parise, R. A.; Rettie, A. E.; Gonzalez, F. J.; Tracy, T. S. Evaluation of atypical cytochrome P450 kinetics with two-substrate models: evidence that multiple substrates can simultaneously bind to cytochrome P450 active sites. Biochemistry 1998, 37, 4137-4147.
75. Szklarz, G. D.; Halpert, J. R. Molecular modeling of cytochrome P450 3A4. J. Comput. Aided Mol. Des. 1997, 11, 265-272.
76. De Rienzo, F.; Fanelli, F.; Menziani, M. C.; De Benedetti, P. G. Theoretical investigation of substrate specificity for cytochromes P450 IA2, P450 IID6 and P450 IIIA4. J. Comput. Aided Mol. Des. 2000, 14, 93-116.
77. Domanski, T. L.; He, Y. A.; Khan, K. K.; Roussel, F.; Wang, Q.; Halpert, J. R. Phenylalanine and tryptophan scanning mutagenesis of CYP3A4 substrate recognition site residues and effect on substrate oxidation and cooperativity. Biochemistry 2001, 40, 10150-10160.
78. Shou, M.; Grogan, J.; Mancewicz, J. A.; Krausz, K. W.; Gonzalez, F. J.; Gelboin, H. V.; Korzekwa, K. R. Activation of CYP3A4: Evidence for the simultaneous binding of two substrates in a cytochrome P450 active site. Biochemistry 1994, 33, 6450-6455.
79. Hosea, N. A.; Miller, G. P.; Guengerich, F. P. Elucidation of distinct ligand binding sites for cytochrome P450 3A4. Biochemistry 2000, 39, 5929-5939.
80. Kenworthy, K. E.; Bloomer, J. C.; Clarke, S. E.; Houston, J. B. CYP3A4 drug interactions: correlation of 10 in vitro probe substrates. Br. J. Clin. Pharmacol. 1999, 48, 716-727.
81. Wang, R. W.; Newton, D. J.; Liu, N.;. Atkins, W. M.; Lu, A. Y. Human cytochrome P-450 3A4: in vitro drug-drug interaction patterns are substrate-dependent. Drug Metab. Dispos. 2000, 28, 360-366.
82. Stresser, D. M.; Blanchard, A. P.; Turner, S. D.; Erve, J. C.; Dandeneau, A. A.; Miller, V. P.; Crespi, C. L. Substrate-dependent modulation of CYP3A4 catalytic activity: analysis of 27 test compounds with four fluorometric substrates. Drug Metab. Dispos. 2000, 28, 1440-1448
83. Ekins, S.; Bravi, G.; Wikel, J. H.; Wrighton, S. A. Three-dimensional-quantitative structure activity relationship analysis of cytochrome P-450 3A4 substrates. J. Pharmacol. Exp. Ther. 1999, 291, 424-433.
84. Ekins, S.; Bravi, G.; Binkley, S.; Gillespie, J. S.; Ring, B. J.; Wikel, J. H.; Wrighton, S. A. Three- and four-dimensional quantitative structure activity relationship analyses of cytochrome P-450 3A4 inhibitors. J. Pharmacol. Exp. Ther. 1999, 290, 429-438.
85. Wanchana, S.; Yamashita, F.; Hashida, M. QSAR analysis of the inhibition of recombinant CYP 3A4 activity by structurally diverse compounds using a genetic algorithm-combined partial least squares method. Pharm. Res. 2003, 20, 1401-1408.
86. Cruciani, G.; Pastor, M.; Guba, W. VolSurf: a new tool for the pharmacokinetic optimization of lead compounds. Eur. J. Pharm. Sci. 2000, 11 Suppl 2, S29-39.
87. Crivori, P.; Zamora, I.; Speed, B.; Orrenius, C.; Poggesi, I. Model based on GRID-derived descriptors for estimating CYP3A4 enzyme stability of potential drug candidates. J. Comput. Aided Mol. Des. 2004, 18, 155-166.
88. Kriegl, J. M.; Eriksson, L.; Arnhold, T.; Beck, B.; Johansson, E.; Fox, T. Multivariate modeling of cytochrome P450 3A4 inhibition. Eur. J. Pharm. Sci. 2005, 24, 451-463
89. Kriegl, J. M.; Arnhold, T.; Beck, B.; Fox, T. A support vector machine approach to classify human cytochrome P450 3A4 inhibitors. J. Comput. Aided Mol. Des. 2005, 19, 189-201.
90. Vapnik, V. N. The nature of statistical learning theory; Springer: New York, 1995.
91. Korolev, D.; Balakin, K. V.; Nikolsky, Y.; Kirillov, E.; Ivanenkov, Y. A.; Savchuk, N. P.; Ivashchenko, A. A.; Nikolskaya, T. Modeling of human cytochrome p450-mediated drug metabolism using unsupervised machine learning approach. J. Med. Chem. 2003, 46, 3631-3643.
92. Balakin, K. V.; Ekins, S.; Bugrim, A.; Ivanenkov, Y. A.; Korolev, D. et al. Kohonen maps for prediction of binding to human cytochrome P450 3A4. Drug Metab. Dispos. 2004, 32, 1183-1189.
93. Balakin, K. V.; Ekins, S.; Bugrim, A.; Ivanenkov, Y. A.; Korolev, D.; Nikolsky, Y. V.; Ivashchenko, A. A.; Savchuk, N. P.; Nikolskaya, T. Quantitative structure-metabolism relationship modeling of metabolic N-dealkylation reaction rates. Drug Metab. Dispos. 2004, 32, 1111-1120.
94. Molnar, L.; Keseru, G. M. A neural network based virtual screening of cytochrome P450 3A4 inhibitors. Bioorg. Med. Chem. Lett. 2002, 12, 419-421.
95. Ekins, S.; Berbaum, J.; Harrison, R. K. Generation and validation of rapid computational filters for cyp2d6 and cyp3a4. Drug Metab. Dispos. 2003, 31, 1077-1080.
96. Dietterich, T. G. Ensemble learning. In The handbook of brain theory and neural networks; 2nd ed.; MIT Press: Cambridge, MA, 2003; pp 405-408.
97. Breiman, L. Using iterated bagging to debias regressions. Mach. Learn. 2001, 45, 261-277.
98. Breiman, L. Bagging Predictors. Mach. Learn. 1996, 24, 123-140.
99. Freund, Y.; Schapire, R. E. A decision-theoretic generalization of on-line learning and an application to boosting. J. Comput. Syst. Sci. 1997, 55, 119-139.
100. Breiman, L. Random forests. Mach. Learn. 2001, 45, 5-32.
101. Yap, C. W.; Chen, Y. Z. Prediction of cytochrome P450 3A4, 2D6, and 2C9 inhibitors and substrates by using support vector machines. J. Chem. Inf. Model. 2005, 45, 982-992.
102. Durant, J. L.; Leland, B. A.; Henry, D. R.; Nourse, J. G. Reoptimization of MDL keys for use in drug discovery. J. Chem. Inf. Comput. Sci. 2002, 42, 1273-1280.
103. Arimoto, R.; Prasad, M. A.; Gifford, E. M. Development of CYP3A4 inhibition models: comparisons of machine-learning techniques and molecular descriptors. J. Biomol. Screen. 2005, 10, 197-205.
104. O'Brien, S. E.; de Groot, M. J. Greater than the sum of its parts: combining models for useful ADMET prediction. J. Med. Chem. 2005, 48, 1287-1291.