In silico modeling of P450 substrates, inhibitors, activators, and inducers

Combinatorial Chemistry and High Throughput Screening

Volumn 14, Issue 5, 2011, Pages 396-416

  DeLisle, Robert Kirk ^a   Otten, Jennifer ^a   Rhodes, Susan ^a  

^a ARRAY BIOPHARMA INC   (United States)

Author keywords

Cytochrome P450; Drug metabolism.; Molecular modeling

Indexed keywords

CELL NUCLEUS RECEPTOR; CELL NUCLEUS RECEPTOR AHR; CELL NUCLEUS RECEPTOR CAR; CYTOCHROME P450; CYTOCHROME P450 1A2; CYTOCHROME P450 2B6; CYTOCHROME P450 2C19; CYTOCHROME P450 2C8; CYTOCHROME P450 2C9; CYTOCHROME P450 2D6; CYTOCHROME P450 3A4; PREGNANE X RECEPTOR; UNCLASSIFIED DRUG;

ARTICLE; COMPUTER MODEL; CRYSTAL STRUCTURE; ENZYME ACTIVATION; ENZYME ACTIVITY; ENZYME INHIBITION; ENZYME STRUCTURE; GENE CONTROL; GENE EXPRESSION; HUMAN; NONHUMAN; PRIORITY JOURNAL; PROTEIN EXPRESSION; PROTEIN FUNCTION;

COMPUTATIONAL BIOLOGY; COMPUTER SIMULATION; CYTOCHROME P-450 ENZYME SYSTEM; DRUG DISCOVERY; MODELS, BIOLOGICAL; PHARMACEUTICAL PREPARATIONS;

EID: 79955739454     PISSN: 13862073     EISSN: None     Source Type: Journal    
DOI: 10.2174/138620711795508377     Document Type: Article

References (162)

1. Shimada, T.; Martin, M. V.; Pruess-Schwartz, D.; Marnett, L. J.; Guengerich, F. P. Roles of individual human cytochrome P-450 enzymes in the bioactivation of benzo(a)pyrene, 7,8-dihydroxy-7,8-dihydrobenzo(a)pyrene, and other dihydrodiol derivatives of polycyclic aromatic hydrocarbons. Cancer Res., 1989, 49 (22), 6304-6312. (Pubitemid 20000928)
2. Guengerich, F. P.; Turvy, C. G. Comparison of levels of several human microsomal cytochrome P-450 enzymes and epoxide hydrolase in normal and disease states using immunochemical analysis of surgical liver samples. J. Pharmacol. Exp. Ther., 1991, 256 (3), 1189-1194.
3. 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 (1), 414-423. (Pubitemid 24229655)
4. Zuber, R.; Anzenbacherova, E.; Anzenbacher, P. Cytochromes P450 and experimental models of drug metabolism. J. Cell Mol. Med., 2002, 6 (2), 189-198. (Pubitemid 44137197)
5. Conney, A. H. Induction of microsomal enzymes by foreign chemicals and carcinogenesis by polycyclic aromatic hydrocarbons: G. H. A. Clowes Memorial Lecture. Cancer Res., 1982, 42 (12), 4875-4917. (Pubitemid 13223122)
6. Kim, D.; Guengerich, F. P. Cytochrome P450 activation of arylamines and heterocyclic amines. Annu. Rev. Pharmacol. Toxicol., 2005, 45, 27-49. (Pubitemid 40261797)
7. Gelboin, H. V. Benzo[alpha]pyrene metabolism, activation and carcinogenesis: role and regulation of mixed-function oxidases and related enzymes. Physiol. Rev., 1980, 60 (4), 1107-1166.
8. Costas, I., Cytochromes P450: Role in the metabolism and toxicity of drugs and other xenobiotics. RSC Publishing: Cambridge, UK, 2008; p 400.
9. Flockhart, D. Drug Interactions: Cytochrome P450 Drug Interaction Table. http://medicine.iupui.edu/clinpharm/ddis/table. asp (accessed 1 May, 2010).
10. Fuhr, U.; Strobl, G.; Manaut, F.; Anders, E. M.; Sorgel, F.; Lopezde-Brinas, E.; Chu, D. T.; Pernet, A. G.; Mahr, G.; Sanz, F.; et al. Quinolone antibacterial agents: relationship between structure and in vitro inhibition of the human cytochrome P450 isoform CYP1A2. Mol. Pharmacol., 1993, 43 (2), 191-199. (Pubitemid 23055062)
11. Sanz, F.; Lopez-de-Brinas, E.; Rodrigues, J.; Manaut, F. Theoretical study on the metabolism of caffeine by cytochrome P450 1A2 and its inhibition. QSAR, 1994, 13 (3), 281-284. (Pubitemid 24319343)
12. 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 (9), 1369-1375. (Pubitemid 28298516)
13. Moon, T.; Chi, M. H.; Yoon, C. N.; Choi, Y.-S. Quantitative structure-actitivity relationships (QSAR) study of flavonoid derivatives for inhibition of cytochrome P450 1A2. QSAR, 2000, 19, 257-263. (Pubitemid 30428231)
14. Kless, A.; Eitrich, T., Cytochrome P450 classification of drugs with support vector machines implementing the nearest point algorithm. Lecture Notes in Computer Science 2004, 3303, 191-205. (Pubitemid 41050332)
15. Burton, J.; Ijjaali, I.; Barberan, O.; Petitet, F.; Vercauteren, D. P.; Michel, A. Recursive partitioning for the prediction of cytochromes P450 2D6 and 1A2 inhibition: importance of the quality of the dataset. J. Med. Chem., 2006, 49 (21), 6231-6240. (Pubitemid 44595200)
16. Labute, P., A widely applicable set of descriptors. J Mol. Graph. Model., 2000, 18 (4-5), 464-477. (Pubitemid 32260549)
17. 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 (11), 3808-3815. (Pubitemid 40776855)
18. Chohan, 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 (16), 5154-5161. (Pubitemid 41113903)
19. Hammann, F.; Gutmann, H.; Baumann, U.; Helma, C.; Drewe, J. Classification of cytochrome p(450) activities using machine learning methods. Mol. Pharm., 2009, 6 (6), 1920-1926.
20. Gleeson, M. P.; Davis, A. M.; Chohan, K. K.; Paine, S. W.; Boyer, S.; Gavaghan, C. L.; Arnby, C. H.; Kankkonen, C.; Albertson, N. Generation of in-silico cytochrome P450 1A2, 2C9, 2C19, 2D6, and 3A4 inhibition QSAR models. J. Comput. Aided Mol. Des., 2007, 21 (10-11), 559-573. (Pubitemid 50005007)
21. Vasanthanathan, P.; Taboureau, O.; Oostenbrink, C.; Vermeulen, N. P.; Olsen, L.; Jorgensen, F. S. Classification of cytochrome P450 1A2 inhibitors and noninhibitors by machine learning techniques. Drug Metab. Dispos., 2009, 37 (3), 658-664.
22. 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 (1), 93-116. (Pubitemid 30103825)
23. Lozano, J. J.; Pastor, M.; Cruciani, G.; Gaedt, K.; Centeno, N. B.; Gago, F.; Sanz, F. 3D-QSAR methods on the basis of ligandreceptor complexes. Application of COMBINE and GRID/GOLPE methodologies to a series of CYP1A2 ligands. J. Comput. Aided Mol. Des., 2000, 14 (4), 341-353. (Pubitemid 30219396)
24. Iori, F.; da Fonseca, R.; Ramos, M. J.; Menziani, M. C. Theoretical quantitative structure-activity relationships of flavone ligands interacting with cytochrome P450 1A1 and 1A2 isozymes. Bioorg. Med. Chem., 2005, 13 (14), 4366-4374. (Pubitemid 40813224)
25. Sansen, S.; Yano, J. K.; Reynald, R. L.; Schoch, G. A.; Griffin, K. J.; Stout, C. D.; Johnson, E. F. Adaptations for the oxidation of polycyclic aromatic hydrocarbons exhibited by the structure of human P450 1A2. J. Biol. Chem., 2007, 282 (19), 14348-14355. (Pubitemid 47100434)
26. Rydberg, P.; Vasanthanathan, P.; Oostenbrink, C.; Olsen, L. Fast prediction of cytochrome P450 mediated drug metabolism. ChemMedChem., 2009, 4 (12), 2070-2079.
27. Wang, H.; Negishi, M., Transcriptional regulation of cytochrome p450 2B genes by nuclear receptors. Curr. Drug Metab., 2003, 4 (6), 515-525. (Pubitemid 37536872)
28. Faucette, S. R.; Wang, H.; Hamilton, G. A.; Jolley, S. L.; Gilbert, D.; Lindley, C.; Yan, B.; Negishi, M.; LeCluyse, E. L. Regulation of CYP2B6 in primary human hepatocytes by prototypical inducers. Drug Metab. Dispos., 2004, 32 (3), 348-358. (Pubitemid 38263894)
29. Code, E. L.; Crespi, C. L.; Penman, B. W.; Gonzalez, F. J.; Chang, T. K.; Waxman, D. J. Human cytochrome P4502B6: interindividual hepatic expression, substrate specificity, and role in procarcinogen activation. Drug Metab. Dispos., 1997, 25 (8), 985-993. (Pubitemid 27357697)
30. Lamba, V.; Lamba, J.; Yasuda, K.; Strom, S.; Davila, J.; Hancock, M. L.; Fackenthal, J. D.; Rogan, P. K.; Ring, B.; Wrighton, S. A.; Schuetz, E. G. Hepatic CYP2B6 expression: gender and ethnic differences and relationship to CYP2B6 genotype and CAR (constitutive androstane receptor) expression. J. Pharmacol. Exp. Ther., 2003, 307 (3), 906-922. (Pubitemid 37494207)
31. Schmidt, R.; Baumann, F.; Hanschmann, H.; Geissler, F.; Preiss, R. Gender difference in ifosfamide metabolism by human liver microsomes. Eur. J. Drug Metab. Pharmacokinet., 2001, 26 (3), 193-200. (Pubitemid 32988561)
32. Xie, W.; Evans, R. M., Orphan nuclear receptors: the exotics of xenobiotics. J. Biol. Chem., 2001, 276 (41), 37739-37742.
33. Faucette, S. R.; Hawke, R. L.; Lecluyse, E. L.; Shord, S. S.; Yan, B.; Laethem, R. M.; Lindley, C. M., Validation of bupropion hydroxylation as a selective marker of human cytochrome P450 2B6 catalytic activity. Drug Metab. Dispos., 2000, 28 (10), 1222-1230.
34. Lang, T.; Klein, K.; Fischer, J.; Nussler, A. K.; Neuhaus, P.; Hofmann, U.; Eichelbaum, M.; Schwab, M.; Zanger, U. M. Extensive genetic polymorphism in the human CYP2B6 gene with impact on expression and function in human liver. Pharmacogenetics, 2001, 11 (5), 399-415. (Pubitemid 32656581)
35. Nelson, D. R.; Koymans, L.; Kamataki, T.; Stegeman, J. J.; Feyereisen, R.; Waxman, D. J.; Waterman, M. R.; Gotoh, O.; Coon, M. J.; Estabrook, R. W.; Gunsalus, I. C.; Nebert, D. W. P450 superfamily: update on new sequences, gene mapping, accession numbers and nomenclature. Pharmacogenetics, 1996, 6 (1), 1-42. (Pubitemid 26096749)
36. Grimm, S. W.; Einolf, H. J.; Hall, S. D.; He, K.; Lim, H. K.; Ling, K. H.; Lu, C.; Nomeir, A. A.; Seibert, E.; Skordos, K. W.; Tonn, G. R.; Van Horn, R.; Wang, R. W.; Wong, Y. N.; Yang, T. J.; Obach, R. S. The conduct of in vitro studies to address timedependent inhibition of drug-metabolizing enzymes: a perspective of the pharmaceutical research and manufacturers of America. Drug Metab. Dispos., 2009, 37 (7), 1355-1370.
37. Walsky, R. L.; Obach, R. S., Validated assays for human cytochrome P450 activities. Drug Metab. Dispos., 2004, 32 (6), 647-660. (Pubitemid 38668158)
38. Ekins, S.; Bravi, G.; Ring, B. J.; Gillespie, T. A.; Gillespie, J. S.; Vandenbranden, M.; Wrighton, S. A.; Wikel, J. H. Threedimensional quantitative structure activity relationship analyses of substrates for CYP2B6. J. Pharmacol. Exp. Ther., 1999, 288 (1), 21-29. (Pubitemid 29113468)
39. Lewis, D. F.; Lake, B. G.; Dickins, M.; Eddershaw, P. J.; Tarbit, M. H.; Goldfarb, P. S. Molecular modelling of CYP2B6, the human CYP2B isoform, by homology with the substrate-bound CYP102 crystal structure: evaluation of CYP2B6 substrate characteristics, the cytochrome b5 binding site and comparisons with CYP2B1 and CYP2B4. Xenobiotica, 1999, 29 (4), 361-393. (Pubitemid 29204284)
40. Wang, Q.; Halpert, J. R., Combined three-dimensional quantitative structure-activity relationship analysis of cytochrome P450 2B6 substrates and protein homology modeling. Drug Metab Dispos 2002, 30 (1), 86-95. (Pubitemid 34016945)
41. Ekins, S.; Iyer, M.; Krasowski, M. D.; Kharasch, E. D. Molecular characterization of CYP2B6 substrates. Curr. Drug Metab., 2008, 9 (5), 363-373. (Pubitemid 352025191)
42. Leong, M. K.; Chen, Y. M.; Chen, T. H. Prediction of human cytochrome P450 2B6-substrate interactions using hierarchical support vector regression approach. J. Comput. Chem., 2009, 30 (12), 1899-1909.
43. Gay, S. C.; Shah, M. B.; Talakad, J. C.; Maekawa, K.; Roberts, A. G.; Wilderman, P. R.; Sun, L.; Yang, J. Y.; Huelga, S. C.; Hong, W. X.; Zhang, Q.; Stout, C. D.; Halpert, J. R. Crystal structure of a cytochrome P450 2B6 genetic variant in complex with the inhibitor 4-(4-chlorophenyl)imidazole at 2.0-A resolution. Mol. Pharmacol., 2010, 77 (4), 529-538.
44. Goldstein, J. A. Clinical relevance of genetic polymorphisms in the human CYP2C subfamily. Br. J. Clin. Pharmacol., 2001, 52 (4), 349-355. (Pubitemid 32939439)
45. Romkes, M.; Faletto, M. B.; Blaisdell, J. A.; Raucy, J. L.; Goldstein, J. A. Cloning and expression of complementary DNAs for multiple members of the human cytochrome P450IIC subfamily. Biochemistry, 1991, 30 (13), 3247-3255.
46. Delozier, T. C.; Kissling, G. E.; Coulter, S. J.; Dai, D.; Foley, J. F.; Bradbury, J. A.; Murphy, E.; Steenbergen, C.; Zeldin, D. C.; Goldstein, J. A. Detection of human CYP2C8, CYP2C9, and CYP2J2 in cardiovascular tissues. Drug Metab. Dispos., 2007, 35 (4), 682-688. (Pubitemid 46513273)
47. Klose, T. S.; Blaisdell, J. A.; Goldstein, J. A. Gene structure of CYP2C8 and extrahepatic distribution of the human CYP2Cs. J. Biochem. Mol. Toxicol., 1999, 13 (6), 289-295. (Pubitemid 129705404)
48. Nishimura, M.; Yaguti, H.; Yoshitsugu, H.; Naito, S.; Satoh, T. Tissue distribution of mRNA expression of human cytochrome P450 isoforms assessed by high-sensitivity real-time reverse transcription PCR. Yakugaku Zasshi, 2003, 123 (5), 369-375. (Pubitemid 41327466)
49. Walsky, R. L.; Gaman, E. A.; Obach, R. S. Examination of 209 drugs for inhibition of cytochrome P450 2C8. J. Clin. Pharmacol., 2005, 45 (1), 68-78.
50. Tanaka, T.; Kamiguchi, N.; Okuda, T.; Yamamoto, Y. Characterization of the CYP2C8 active site by homology modeling. Chem. Pharm. Bull (Tokyo), 2004, 52 (7), 836-841. (Pubitemid 41679574)
51. Ogilvie, B. W.; Zhang, D.; Li, W.; Rodrigues, A. D.; Gipson, A. E.; Holsapple, J.; Toren, P.; Parkinson, A. Glucuronidation converts gemfibrozil to a potent, metabolism-dependent inhibitor of CYP2C8: implications for drug-drug interactions. Drug Metab. Dispos., 2006, 34 (1), 191-197. (Pubitemid 43042661)
52. Melet, A.; Marques-Soares, C.; Schoch, G. A.; Macherey, A. C.; Jaouen, M.; Dansette, P. M.; Sari, M. A.; Johnson, E. F.; Mansuy, D. Analysis of human cytochrome P450 2C8 substrate specificity using a substrate pharmacophore and site-directed mutants. Biochemistry, 2004, 43 (49), 15379-15392. (Pubitemid 39647464)
53. 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 (10), 9497-9503. (Pubitemid 38296017)
54. Aithal, G. P.; Day, C. P.; Kesteven, P. J.; Daly, A. K. Association of polymorphisms in the cytochrome P450 CYP2C9 with warfarin dose requirement and risk of bleeding complications. Lancet, 1999, 353 (9154), 717-719. (Pubitemid 29103806)
55. Goldstein, J. A.; de Morais, S. M., Biochemistry and molecular biology of the human CYP2C subfamily. Pharmacogenetics, 1994, 4 (6), 285-299.
56. Zhang, W.; Ramamoorthy, Y.; Kilicarslan, T.; Nolte, H.; Tyndale, R. F.; Sellers, E. M. Inhibition of cytochromes P450 by antifungal imidazole derivatives. Drug Metab. Dispos., 2002, 30 (3), 314-318. (Pubitemid 34175023)
57. Baldwin, S. J.; Bloomer, J. C.; Smith, G. J.; Ayrton, A. D.; Clarke, S. E.; Chenery, R. J., Ketoconazole and sulphaphenazole as the respective selective inhibitors of P4503A and 2C9. Xenobiotica 1995, 25 (3), 261-70.
58. Kumar, V.; Wahlstrom, J. L.; Rock, D. A.; Warren, C. J.; Gorman, L. A.; Tracy, T. S. CYP2C9 inhibition: impact of probe selection and pharmacogenetics on in vitro inhibition profiles. Drug Metab. Dispos., 2006, 34 (12), 1966-1975. (Pubitemid 44837757)
59. 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 (33), 10365-10375.
60. 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 (50), 16205-16212.
61. 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 (2), 260-266. (Pubitemid 26063913)
62. Jones, J. P.; He, M.; Trager, W. F.; Rettie, A. E., Threedimensional quantitative structure-activity relationship for inhibitors of cytochrome P4502C9. Drug Metab. Dispos., 1996, 24 (1), 1-6. (Pubitemid 26029580)
63. 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 (8), 994-1002. (Pubitemid 30612621)
64. Morsman, J. M.; Smith, D. A.; Jones, B. C.; Hawksworth, G. M. Role of hydrogen-bonding in substrate structure-activity relationships for CYP2C9. ISSX Proceedings, 1995, 8, 259.
65. 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 (15), 2789-2796. (Pubitemid 30599636)
66. 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 (4), 909-919. (Pubitemid 32274021)
67. Afzelius, L.; Masimirembwa, C. M.; Karlen, A.; Andersson, 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 (7), 443-458. (Pubitemid 36018696)
68. 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 (4), 907-914. (Pubitemid 38176793)
69. 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 (10), 1983-1993. (Pubitemid 34477712)
70. Zamora, I.; Afzelius, L.; Cruciani, G., Predicting drug metabolism: a site of metabolism prediction tool applied to the cytochrome P450 2C9. J Med Chem 2003, 46 (12), 2313-24. (Pubitemid 36637916)
71. 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 (6947), 464-468. (Pubitemid 36917499)
72. Wester, M. R.; Yano, J. K.; Schoch, G. A.; Yang, C.; Griffin, K. J.; Stout, C. D.; Johnson, E. F. The structure of human cytochrome P450 2C9 complexed with flurbiprofen at 2.0-A resolution. J. Biol. Chem., 2004, 279 (34), 35630-35637. (Pubitemid 39100565)
73. Locuson, C. W., 2nd; Rock, D. A.; Jones, J. P. Quantitative binding models for CYP2C9 based on benzbromarone analogues. Biochemistry, 2004, 43 (22), 6948-6958. (Pubitemid 38720513)
74. 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 (4), 982-992. (Pubitemid 41156697)
75. Yasuo, K.; Yamaotsu, N.; Gouda, H.; Tsujishita, H.; Hirono, S. Structure-based CoMFA as a predictive model - CYP2C9 inhibitors as a test case. J. Chem. Inf. Model., 2009, 49 (4), 853-864.
76. Ahlstrom, M. M.; Ridderstrom, M.; Zamora, I. CYP2C9 structuremetabolism relationships: substrates, inhibitors, and metabolites. J. Med. Chem., 2007, 50 (22), 5382-5391.
77. Sykes, M. J.; McKinnon, R. A.; Miners, J. O. Prediction of metabolism by cytochrome P450 2C9: alignment and docking studies of a validated database of substrates. J. Med. Chem., 2008, 51 (4), 780-791. (Pubitemid 351304687)
78. Tarcsay, A.; Kiss, R.; Keseru, G. M. Site of metabolism prediction on cytochrome P450 2C9: a knowledge-based docking approach. J. Comput. Aided Mol. Des., 2010, 24 (5), 399-408.
79. Hudelson, M. G.; Ketkar, N. S.; Holder, L. B.; Carlson, T. J.; Peng, C. C.; Waldher, B. J.; Jones, J. P. High confidence predictions of drug-drug interactions: predicting affinities for cytochrome P450 2C9 with multiple computational methods. J. Med. Chem., 2008, 51 (3), 648-654. (Pubitemid 351252292)
80. Hudelson, M. G.; Jones, J. P. Line-walking method for predicting the inhibition of P450 drug metabolism. J. Med. Chem., 2006, 49 (14), 4367-4373. (Pubitemid 44036680)
81. Rodrigues, A. D.; Rushmore, T. H. Cytochrome P450 pharmacogenetics in drug development: in vitro studies and clinical consequences. Curr. Drug Metab., 2002, 3 (3), 289-309. (Pubitemid 34625041)
82. Flockhart, D. Drug Interactions: Cytochrome P450 Drug Interaction Table. http://medicine.iupui.edu/clinpharm/ddis/table.asp (accessed 18 June, 2010).
83. Foti, R. S.; Wahlstrom, J. L. CYP2C19 inhibition: the impact of substrate probe selection on in vitro inhibition profiles. Drug Metab. Dispos., 2008, 36 (3), 523-528. (Pubitemid 351397977)
84. Lock, R. E.; Jones, B. C.; Smith, D. A.; Hawksworth, G. M., Investigation of substrate structure activity relationships (SSAR) for cytochrome P450 2C19. Br. J. Clin. Pharmacol., 1998, 45, 511P.
85. Locuson, C. W., 2nd; Suzuki, H.; Rettie, A. E.; Jones, J. P. Charge and substituent effects on affinity and metabolism of benzbromarone-based CYP2C19 inhibitors. J. Med. Chem., 2004, 47 (27), 6768-6776. (Pubitemid 40053765)
86. Hutzler, J. M.; Walker, G. S.; Wienkers, L. C. Inhibition of cytochrome P450 2D6: structure-activity studies using a series of quinidine and quinine analogues. Chem. Res. Toxicol., 2003, 16 (4), 450-459. (Pubitemid 36514502)
87. Mahgoub, A.; Idle, J. R.; Dring, L. G.; Lancaster, R.; Smith, R. L. Polymorphic hydroxylation of Debrisoquine in man. Lancet, 1977, 2 (8038), 584-586. (Pubitemid 8176607)
88. 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 (5), 2116-2122. (Pubitemid 15024394)
89. 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 (5), 449-464. (Pubitemid 16076723)
90. 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 (2), 211-219.
91. Islam, S. A.; Wolf, C. R.; Lennard, M. S.; Sternberg, M. J. A three-dimensional molecular template for substrates of human cytochrome P450 involved in debrisoquine 4-hydroxylation. Carcinogenesis, 1991, 12 (12), 2211-2219.
92. 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 (9), 1136-1145. (Pubitemid 23159287)
93. 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 (7), 1079-1091. (Pubitemid 26347960)
94. 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 (4), 357-368. (Pubitemid 27199381)
95. 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 (1), 41-48. (Pubitemid 27044906)
96. de Groot, M. J.; Ackland, M. J.; Horne, 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 (9), 1515-1524. (Pubitemid 29226723)
97. 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 (20), 4062-4070. (Pubitemid 29483023)
98. Kemp, C. A.; Flanagan, J. U.; van Eldik, A. J.; Marechal, J. D.; Wolf, C. R.; Roberts, G. C.; Paine, M. J.; Sutcliffe, M. J. Validation of model of cytochrome P450 2D6: an in silico tool for predicting metabolism and inhibition. J. Med. Chem., 2004, 47 (22), 5340-5346. (Pubitemid 39382784)
99. Snyder, R.; Sangar, R.; Wang, J.; Ekins, S. Three-dimensional quantitative structure activity relationship for Cyp2D6 substrates. QSAR, 2002, 21, 357-368. (Pubitemid 35177919)
100. Rowland, P.; Blaney, F. E.; Smyth, M. G.; Jones, J. J.; Leydon, V. R.; Oxbrow, A. K.; Lewis, C. J.; Tennant, M. G.; Modi, S.; Eggleston, D. S.; Chenery, R. J.; Bridges, A. M. Crystal structure of human cytochrome P450 2D6. J. Biol. Chem., 2006, 281 (11), 7614-7622. (Pubitemid 43847532)
101. 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 (10), 1111-1120. (Pubitemid 39287585)
102. 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 (4), 1287-1291. (Pubitemid 40270476)
103. Ekins, S.; Berbaum, J.; Harrison, R. K., Generation and validation of rapid computational filters for cyp2d6 and cyp3a4. Drug Metab. Dispos., 2003, 31 (9), 1077-1080. (Pubitemid 37048276)
104. Susnow, R. G.; Dixon, S. L., Use of robust classification techniques for the prediction of human cytochrome P450 2D6 inhibition. J. Chem. Inf. Comput. Sci., 2003, 43 (4), 1308-1315.
105. Kriegl, J. M.; Arnhold, T.; Beck, B.; Fox, T. Prediction of human cytochrome P450 inhibition using support vector machines. QSAR and Combinatorial Science, 2005, 24, 491-502. (Pubitemid 40839677)
106. Jensen, B. F.; Vind, C.; Padkjaer, S. B.; Brockhoff, P. B.; Refsgaard, H. H. In silico prediction of cytochrome P450 2D6 and 3A4 inhibition using Gaussian kernel weighted k-nearest neighbor and extended connectivity fingerprints, including structural fragment analysis of inhibitors versus noninhibitors. J. Med. Chem., 2007, 50 (3), 501-511. (Pubitemid 46239784)
107. Ringsted, T.; Nikolov, N.; Jensen, G. E.; Wedebye, E. B.; Niemela, J. QSAR models for P450 (2D6) substrate activity. SAR QSAR Environ. Res., 2009, 20 (3-4), 309-325.
108. Kolars, J. C.; Schmiedlin-Ren, P.; Schuetz, J. D.; Fang, C.; Watkins, P. B. Identification of rifampin-inducible P450IIIA4 (CYP3A4) in human small bowel enterocytes. J. Clin. Invest., 1992, 90 (5), 1871-1878.
109. Kato, M.; Chiba, K.; Hisaka, A.; Ishigami, M.; Kayama, M.; Mizuno, N.; Nagata, Y.; Takakuwa, S.; Tsukamoto, Y.; Ueda, K.; Kusuhara, H.; Ito, K.; Sugiyama, Y. The intestinal first-pass metabolism of substrates of CYP3A4 and P-glycoproteinquantitative analysis based on information from the literature. Drug Metab. Pharmacokinet., 2003, 18 (6), 365-372.
110. Atkins, W. M. Non-Michaelis-Menten kinetics in cytochrome P450-catalyzed reactions. Annu. Rev. Pharmacol. Toxicol., 2005, 45, 291-310. (Pubitemid 40261807)
111. Eagling, V. A.; Back, D. J.; Barry, M. G. Differential inhibition of cytochrome P450 isoforms by the protease inhibitors, ritonavir, saquinavir and indinavir. Br. J. Clin. Pharmacol., 1997, 44 (2), 190-194. (Pubitemid 27327076)
112. 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 (1), 429-438. (Pubitemid 29302353)
113. Pichard, L.; Domergue, J.; Fourtanier, G.; Koch, P.; Schran, H. F.; Maurel, P., Metabolism of the new immunosuppressor cyclosporin G by human liver cytochromes P450. Biochem Pharmacol 1996, 51 (5), 591-8. (Pubitemid 126353249)
114. Pichard, L.; Fabre, I.; Fabre, G.; Domergue, J.; Saint Aubert, B.; Mourad, G.; Maurel, P. Cyclosporin A drug interactions. Screening for inducers and inhibitors of cytochrome P-450 (cyclosporin A oxidase) in primary cultures of human hepatocytes and in liver microsomes. Drug Metab. Dispos., 1990, 18 (5), 595-606. (Pubitemid 20348846)
115. Ekins, S.; Bravi, G.; Wikel, J. H.; Wrighton, S. A. Threedimensional- quantitative structure activity relationship analysis of cytochrome P-450 3A4 substrates. J. Pharmacol. Exp. Ther., 1999, 291 (1), 424-433. (Pubitemid 29451619)
116. 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 (5684), 683-686. (Pubitemid 39006760)
117. 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 (37), 38091-38094. (Pubitemid 39295952)
118. Ekroos, M.; Sjogren, T. Structural basis for ligand promiscuity in cytochrome P450 3A4. Proc. Natl. Acad. Sci. USA, 2006, 103 (37), 13682-13687. (Pubitemid 44413967)
119. Singh, S. B.; Shen, L. Q.; Walker, M. J.; Sheridan, R. P. A model for predicting likely sites of CYP3A4-mediated metabolism on drug-like molecules. J. Med. Chem., 2003, 46 (8), 1330-1336. (Pubitemid 36512698)
120. Zhou, D.; Afzelius, L.; Grimm, S. W.; Andersson, T. B.; Zauhar, R. J.; Zamora, I. Comparison of methods for the prediction of the metabolic sites for CYP3A4-mediated metabolic reactions. Drug Metab. Dispos., 2006, 34 (6), 976-983. (Pubitemid 43763754)
121. 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 (3), 189-201. (Pubitemid 40974006)
122. Zhou, D.; Liu, R.; Otmani, S. A.; Grimm, S. W.; Zauhar, R. J.; Zamora, I. Rapid classification of CYP3A4 inhibition potential using support vector machine approach. Letters in Drug Design & Discovery, 2007, 4, 192-200. (Pubitemid 46474159)
123. Molnar, L.; Keseru, G. M. A neural network based virtual screening of cytochrome P450 3A4 inhibitors. Bioorg. Med. Chem. Lett., 2002, 12 (3), 419-421. (Pubitemid 34113917)
124. Zuegge, J.; Fechner, U.; Roche, O.; Parrott, N. J.; Engkvist, O.; Schneider, G. A fast virtual screening filter for cytochrome P450 3A4 inhibition liability of compound libraries. QSAR 2002, (249-56). (Pubitemid 34951595)
125. Merkwirth, C.; Mauser, H.; Schulz-Gasch, T.; Roche, O.; Stahl, M.; Lengauer, T. Ensemble methods for classification in cheminformatics. J. Chem. Inf. Comput. Sci., 2004, 44 (6), 1971-1978.
126. 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 (3), 197-205. (Pubitemid 40617157)
127. 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 (5), 451-463. (Pubitemid 40387259)
128. Choi, I.; Kim, S. Y.; Kim, H.; Kang, N. S.; Bae, M. A.; Yoo, S. E.; Jung, J.; No, K. T. Classification models for CYP450 3A4 inhibitors and non-inhibitors. Eur. J. Med. Chem., 2009, 44 (6), 2354-2360.
129. Balakin, K. V.; Ekins, S.; Bugrim, A.; Ivanenkov, Y. A.; Korolev, D.; Nikolsky, Y. V.; Skorenko, A. V.; Ivashchenko, A. A.; Savchuk, N. P.; Nikolskaya, T. Kohonen maps for prediction of binding to human cytochrome P450 3A4. Drug Metab. Dispos., 2004, 32 (10), 1183-1189. (Pubitemid 39287594)
130. 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 (3), 155-166. (Pubitemid 39069411)
131. 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 (9), 1401-1408. (Pubitemid 37164048)
132. Mao, B.; Gozalbes, R.; Barbosa, F.; Migeon, J.; Merrick, S.; Kamm, K.; Wong, E.; Costales, C.; Shi, W.; Wu, C.; Froloff, N. QSAR modeling of in vitro inhibition of cytochrome P450 3A4. J. Chem. Inf. Model., 2006, 46 (5), 2125-2134. (Pubitemid 44625983)
133. Lewis, D. F. On the recognition of mammalian microsomal cytochrome P450 substrates and their characteristics: towards the prediction of human p450 substrate specificity and metabolism. Biochem. Pharmacol., 2000, 60 (3), 293-306. (Pubitemid 30336626)
134. 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 (17), 3631-3643. (Pubitemid 36988650)
135. Freitas, R. F.; Bauab, R. L.; Montanari, C. A. Novel application of 2D and 3D-similarity searches to identify substrates among cytochrome P450 2C9, 2D6, and 3A4. J. Chem. Inf. Model., 2010, 50 (1), 97-109.
136. Terfloth, L.; Bienfait, B.; Gasteiger, J. Ligand-based models for the isoform specificity of cytochrome P450 3A4, 2D6, and 2C9 substrates. J. Chem. Inf. Model., 2007, 47 (4), 1688-1701. (Pubitemid 47210071)
137. Alarid, E. T. Lives and times of nuclear receptors. Mol. Endocrinol., 2006, 20 (9), 1972-1981. (Pubitemid 44286698)
138. Germain, P.; Staels, B.; Dacquet, C.; Spedding, M.; Laudet, V. Overview of nomenclature of nuclear receptors. Pharmacol. Rev., 2006, 58 (4), 685-704. (Pubitemid 44833739)
139. Ma, Q. Xenobiotic-activated receptors: from transcription to drug metabolism to disease. Chem. Res. Toxicol., 2008, 21 (9), 1651-1671.
140. Tien, E. S.; Negishi, M. Nuclear receptors CAR and PXR in the regulation of hepatic metabolism. Xenobiotica, 2006, 36 (10-11), 1152-1163. (Pubitemid 44844116)
141. Handschin, C.; Meyer, U. A. Induction of drug metabolism: the role of nuclear receptors. Pharmacol. Rev., 2003, 55 (4), 649-673. (Pubitemid 37504978)
142. Waxman, D. J. P450 gene induction by structurally diverse xenochemicals: central role of nuclear receptors CAR, PXR, and PPAR. Arch. Biochem. Biophys., 1999, 369 (1), 11-23. (Pubitemid 29434534)
143. UniGene. http://www.ncbi.nlm.nih.gov/unigene (accessed 12 June 2010).
144. Maglich, J. M.; Parks, D. J.; Moore, L. B.; Collins, J. L.; Goodwin, B.; Billin, A. N.; Stoltz, C. A.; Kliewer, S. A.; Lambert, M. H.; Willson, T. M.; Moore, J. T. Identification of a novel human constitutive androstane receptor (CAR) agonist and its use in the identification of CAR target genes. J. Biol. Chem., 2003, 278 (19), 17277-17283. (Pubitemid 36799610)
145. Timsit, Y. E.; Negishi, M. CAR and PXR: the xenobiotic-sensing receptors. Steroids, 2007, 72 (3), 231-246. (Pubitemid 46273513)
146. Tompkins, L. M.; Wallace, A. D. Mechanisms of cytochrome P450 induction. J. Biochem. Mol. Toxicol., 2007, 21 (4), 176-181. (Pubitemid 350194377)
147. Faucette, S. R.; Sueyoshi, T.; Smith, C. M.; Negishi, M.; Lecluyse, E. L.; Wang, H. Differential regulation of hepatic CYP2B6 and CYP3A4 genes by constitutive androstane receptor but not pregnane X receptor. J. Pharmacol. Exp. Ther., 2006, 317 (3), 1200-1209. (Pubitemid 43764125)
148. Saini, S. P.; Sonoda, J.; Xu, L.; Toma, D.; Uppal, H.; Mu, Y.; Ren, S.; Moore, D. D.; Evans, R. M.; Xie, W. A novel constitutive androstane receptor-mediated and CYP3Aindependent pathway of bile acid detoxification. Mol. Pharmacol., 2004, 65 (2), 292-300. (Pubitemid 38134256)
149. Staudinger, J. L.; Madan, A.; Carol, K. M.; Parkinson, A. Regulation of drug transporter gene expression by nuclear receptors. Drug Metab. Dispos., 2003, 31 (5), 523-527. (Pubitemid 36444159)
150. Xu, C.; Li, C. Y.; Kong, A. N. Induction of phase I, II and III drug metabolism/transport by xenobiotics. Arch. Pharm. Res., 2005, 28 (3), 249-268; (Pubitemid 44698742)
151. Zhou, J.; Zhang, J.; Xie, W. Xenobiotic nuclear receptor-mediated regulation of UDP-glucuronosyltransferases. Curr. Drug Metab., 2005, 6 (4), 289-298. (Pubitemid 41086763)
152. Ekins, S.; Mirny, L.; Schuetz, E. G. A ligand-based approach to understanding selectivity of nuclear hormone receptors PXR, CAR, FXR, LXRalpha, and LXRbeta. Pharm. Res., 2002, 19 (12), 1788-1800. (Pubitemid 36016024)
153. Jyrkkarinne, J.; Windshugel, B.; Ronkko, T.; Tervo, A. J.; Kublbeck, J.; Lahtela-Kakkonen, M.; Sippl, W.; Poso, A.; Honkakoski, P. Insights into ligand-elicited activation of human constitutive androstane receptor based on novel agonists and threedimensional quantitative structure-activity relationship. J. Med. Chem., 2008, 51 (22), 7181-7192.
154. Xu, R. X.; Lambert, M. H.; Wisely, B. B.; Warren, E. N.; Weinert, E. E.; Waitt, G. M.; Williams, J. D.; Collins, J. L.; Moore, L. B.; Willson, T. M.; Moore, J. T. A structural basis for constitutive activity in the human CAR/RXRalpha heterodimer. Mol. Cell, 2004, 16 (6), 919-928. (Pubitemid 40018402)
155. Ekins, S.; Erickson, J. A. A pharmacophore for human pregnane X receptor ligands. Drug Metab. Dispos., 2002, 30 (1), 96-99. (Pubitemid 34016946)
156. Watkins, R. E.; Wisely, G. B.; Moore, L. B.; Collins, J. L.; Lambert, M. H.; Williams, S. P.; Willson, T. M.; Kliewer, S. A.; Redinbo, M. R. The human nuclear xenobiotic receptor PXR: structural determinants of directed promiscuity. Science, 2001, 292 (5525), 2329-2333. (Pubitemid 32568055)
157. Schuster, D.; Langer, T. The identification of ligand features essential for PXR activation by pharmacophore modeling. J. Chem. Inf. Model, 2005, 45 (2), 431-439. (Pubitemid 40642597)
158. Gao, Y. D.; Olson, S. H.; Balkovec, J. M.; Zhu, Y.; Royo, I.; Yabut, J.; Evers, R.; Tan, E. Y.; Tang, W.; Hartley, D. P.; Mosley, R. T. Attenuating pregnane X receptor (PXR) activation: a molecular modelling approach. Xenobiotica, 2007, 37 (2), 124-138.
159. Watkins, R. E.; Davis-Searles, P. R.; Lambert, M. H.; Redinbo, M. R. Coactivator binding promotes the specific interaction between ligand and the pregnane X receptor. J. Mol. Biol., 2003, 331 (4), 815-828. (Pubitemid 36945439)
160. Watkins, R. E.; Maglich, J. M.; Moore, L. B.; Wisely, G. B.; Noble, S. M.; Davis-Searles, P. R.; Lambert, M. H.; Kliewer, S. A.; Redinbo, M. R. 2.1 A crystal structure of human PXR in complex with the St. John's wort compound hyperforin. Biochemistry, 2003, 42 (6), 1430-1438. (Pubitemid 36205949)
161. Chrencik, J. E.; Orans, J.; Moore, L. B.; Xue, Y.; Peng, L.; Collins, J. L.; Wisely, G. B.; Lambert, M. H.; Kliewer, S. A.; Redinbo, M. R. Structural disorder in the complex of human pregnane X receptor and the macrolide antibiotic rifampicin. Mol. Endocrinol., 2005, 19 (5), 1125-1134. (Pubitemid 40594113)
162. Xue, Y.; Chao, E.; Zuercher, W. J.; Willson, T. M.; Collins, J. L.; Redinbo, M. R. Crystal structure of the PXR-T1317 complex provides a scaffold to examine the potential for receptor antagonism. Bioorg. Med. Chem., 2007, 15 (5), 2156-2166. (Pubitemid 46176620)