Pharmacophore modeling for ADME

Current Topics in Medicinal Chemistry

Volumn 13, Issue 11, 2013, Pages 1327-1342

  Güner, Osman F ^a   Phillip Bowen, J ^a  

^a MERCER UNIVERSITY   (United States)

Author keywords

3D QSAR; ADME profiling; CYP isoenzymes; Cytochrome P450; Drug drug interactions; Metabolic pathways; Pharmacokinetic predictions; Pharmacophore modeling; Predictive ADME Tox; QSAR; Quantitative pharmacophore models

Indexed keywords

ALPRAZOLAM; ARTEMETHER PLUS BENFLUMETOL; ARTEMISININ; ASTEMIZOLE; CAFFEINE; CHLORZOXAZONE; CIMETIDINE; CYTOCHROME P450 1A2; CYTOCHROME P450 2B6; CYTOCHROME P450 2C19; CYTOCHROME P450 2C9; CYTOCHROME P450 2D6; CYTOCHROME P450 2E1; CYTOCHROME P450 3A4; DEBRISOQUINE; DIAZEPAM; DISULFIRAM; ESTRADIOL; FELODIPINE; FLUOXETINE; IMIPRAMINE; KETOCONAZOLE; METOPROLOL; METOPROLOL TARTRATE; MIDAZOLAM MALEATE; NIFEDIPINE; NIMODIPINE; OMEPRAZOLE; ONDANSETRON; PARACETAMOL; PHENYTOIN; PREGNANE X RECEPTOR; PROPAFENONE; PROPRANOLOL; QUINIDINE; RIFAMPICIN; SIMVASTATIN; SPARTEINE; STEROL 14ALPHA DEMETHYLASE; THEOPHYLLINE; TRIAZOLAM; UNINDEXED DRUG; VERAPAMIL; WARFARIN;

CONFORMATION; DRUG ABSORPTION; DRUG DISTRIBUTION; DRUG EXCRETION; DRUG METABOLISM; GRAPEFRUIT JUICE; HUMAN; PHARMACOPHORE; PREDICTION; QUANTITATIVE STRUCTURE ACTIVITY RELATION; REVIEW; TOBACCO; TOXICITY;

BINDING SITES; COMPUTER-AIDED DESIGN; CYTOCHROME P-450 ENZYME SYSTEM; DRUG DESIGN; DRUG EVALUATION, PRECLINICAL; DRUG INTERACTIONS; DRUGS, INVESTIGATIONAL; ENZYME ASSAYS; HUMANS; HYDROPHOBIC AND HYDROPHILIC INTERACTIONS; ISOENZYMES; MODELS, MOLECULAR; QUANTITATIVE STRUCTURE-ACTIVITY RELATIONSHIP; RECEPTORS, STEROID; STATIC ELECTRICITY;

EID: 84881326362     PISSN: 15680266     EISSN: 18734294     Source Type: Journal    
DOI: 10.2174/15680266113139990037     Document Type: Review

References (134)

1. Pharmacophore Perception, Development, and Use in Drug Design; Güner, O. F. Ed.; International University Line: La Jolla, CA, 2000.
2. Pharmacophores and pharmacophore searches; Langer, T.; Hoffmann, R. Eds.; WILEY-VCH: Weinheim, Germany, 2006.
3. Structure-based Drug Discovery; Jhoti, H.; Leach, A. R. Eds.; Springer: Berlin, 2007.
4. Yang, S.-Y. Pharmacophore modeling and applications in drug discovery: challenges and recent advances. Drug Disc Tech, 2010, 15, 444-450.
5. Leach, A. R.; Gillet, V. J.; Lewis, R. A.; Taylor, R. Three-Dimensional Pharmacophore Methods in Drug Discovery. J Med Chem, 2010, 53, 539-558.
6. Khedkar, S. A.; Malde, A. P.; Coutinho, E. J.; Srivastava, S. Pharmacophore Modeling in Drug Discovery and Development: An Overview. Med Chem, 2007, 3, 187-197.
7. Langer, T. Pharmacophores in Drug Research. Molec Inf, 2010, 29, 470-475.
8. Caporuscio, F.; Tafi, A. Pharmacophore modelling: a forty year old approach and its modern synergies. Curr Med Chem, 2011, 18, 2543-2553.
9. Güner, O. F. History and evolution of the pharmacophore concept in computer-aided drug design. Curr Top Med Chem, 2002, 2, 1321-1332.
10. Güner, O. F. The Impact of Pharmacophore Modeling in Drug Design. IDrugs, 2005, 8, 567-572.
11. Ekins, S.; Waller, C. L.; Swaan, P. W.; Cruciani, G.; Wrighton, S. A.; Wikel, J. H. Progress in predicting human ADME parameters in silico. J Pharm Tox Meth, 2000, 44, 251-272.
12. Acharya, C.; Coop, A.; Polli, J. E.; MacKerell Jr, A. D. Recent advances in ligand-based drug design: relevance and utility of the conformationally sampled pharmacophore approach. Curr Comp.-Aided Drug Des, 2011, 7, 10.
13. Bernard, D.; Coop, A.; MacKerell, A. D. Conformationally Sampled Pharmacophore for Peptidic δ Opioid Ligands. J Med Chem, 2005, 48, 7773-7780.
14. Murrall, N. W.; Davies, E. K. Conformational freedom in 3-D databases. 1. Techniques. J Chem Inf Comput Sci, 1990, 30, 312-316.
15. Güner, O. F.; Henry, D. R.; Pearlman, R. S. Use of flexible queries for searching conformationally flexible molecules in databases of three-dimensional structures. J Chem Inf Comput Sci, 1992, 32, 101-109.
16. Moock, T. E.; Henry, D. R.; Ozkabak, A. G.; Alamgir, M. Conformational searching in ISIS/3D databases. J Chem Inf Comput Sci, 1994, 34, 184-189.
17. Smellie, A.; Kahn, S. D.; Teig, S. L. Analysis of conformational coverage. 1. Validation and estimation of coverage. J Chem Inf Comput Sci, 1995, 35, 285-294.
18. Van de Waterbeemd, H.; Gifford, E. ADMET in silico modelling: towards prediction paradise? Nat Rev Drug Disc, 2003, 2, 192-204.
19. Gupta, R. R.; Gifford, E. M.; Liston, T.; Waller, C. L.; Hohman, M.; Bunin, B. A.; Ekins, S. Using Open Source Computational Tools for Predicting Human Metabolic Stability and Additional Absorption, Distribution, Metabolism, Excretion, and Toxicity Properties. Drug Met Disp, 2010, 38, 2083-2090.
20. Clement, O. O.; Güner, O. F. Use of Pharmacophores in Predictive ADME. In Pharmacokinetic Profiling in Drug Research; Testa, B.; Kramer, S. D.; Wunderli-Allenspach, H.; Folkers, G. Eds.; WILEY-VCH: Weinheim, Germany, 2006; pp. 381-393.
21. De Groot, M. J.; Ekins, S. Pharmacophore modeling of cytochromes P450. Adv Drug Deliv Rev, 2002, 54, 367-383.
22. Arimoto, R. Computational models for predicting interactions with cytochrome p450 enzyme. Curr Top Med Chem, 2006, 6, 1609-1618.
23. Schuster, D.; Laggner, C.; Steindl, T. M.; Langer, T. Development and Validation of an In Silico P450 Profiler Based on Pharmacophore Models. Current Drug Discovery Technologies, 2006, 3, 1-48.
24. Kola, I.; Landis, J. Can the pharmaceutical industry reduce attrition rates? Nat Rev Drug Disc, 2004, 3, 711-716.
25. Hansch, C. Quantitative relationships between lipophilic character. Drug Metabolism Reviews 1, 1-14.
26. Cramer, 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.
27. Güner, O.; Clement, O.; Kurogi, Y. Pharmacophore modeling and three dimensional database searching for drug design using catalyst: recent advances. Curr Med Chem, 2004, 11, 2991-3005.
28. Dixon, S. L.; Smondyrev, A. M.; Rao, S. N. PHASE: A Novel Approach to Pharmacophore Modeling and 3D Database Searching. Chem Biol Drug Des, 2006, 67, 370-372.
29. Ekins, S.; de Groot, M. J.; Jones, J. P. Pharmacophore and threedimensional quantitative structure activity relationship methods for modeling cytochrome P450 active sites. Drug Met Disp, 2001, 29, 936-944.
30. Chang, G. W. M.; Kam, P. C. A. The physiological and pharmacological roles of cytochrome P450 isoenzymes. Anaesthesia, 2002, 54, 42-50.
31. Smith, D. A.; Ackland, M. J.; Jones, B. C. Properties of cytochrome P450 isoenzymes and their substrates Part 1: active site characteristics. Drug Disc Tech, 1997, 2, 406-414.
32. Nelson, D. R.; Kamataki, T.; Waxman, D. J.; Guengerich, F. P.; Estabrook, R. W.; Feyereisen, R.; Gonzalez, F. J.; Coon, M. J.; Gunsalus, I. C.; Gotoh, O.; Okuda, K.; Nebert, D. W. The P450 superfamily: update on new sequences, gene mapping, accession numbers, early trivial names of enzymes, and nomenclature. DNA Cell Biol, 1993, 12, 1-51.
33. Nelson, D. R.; Koymans, L.; Kamataki, T.; Stegeman, J. J.; Feyereisen, R.; Waxman, D. J.; Waxman, 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, 1-42.
34. 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 Pharm Exp Thera, 1994, 270, 414-423.
35. Smith, D. A.; Abel, S. M.; Hyland, R.; Jones, B. C. Human cytochrome P450s: selectivity and measurement in vivo. Xenobiotica, 1998, 28, 1095-1128.
36. Gonzales, F. J.; Nebert, D. W. Evolution of the P450 gene superfamily: animal-plant 'warfare ', molecular drive and human genetic differences in drug oxidation. Trends in Genetics, 1990, 6, 182-186.
37. Evans, W. E.; Relling, M. V. Pharmacogenomics: Translating Functional Genomics into Rational Therapeutics. Science, 1999, 286, 487-491.
38. Gao, F.; Johnson, D. L.; Ekins, S.; Janiszewski, J.; Kelly, K. G.; Meyer, R. D.; West, M. Optimizing Higher Throughput Methods to Assess Drug-Drug Interactions for CYP1A2, CYP2C9, CYP2C19, CYP2D6, rCYP2D6, and CYP3A4 In Vitro Using a Single Point IC50. J Biomolec Screen, 2002, 7, 373-382.
39. 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.
40. Bibi, Z. Role of cytochrome P450 in drug interactions. Nut Metab, 2008, 5, 27.
41. Badyal, D. K.; Dadich, A. P. Cytochrome P450 and Drug Interactions. Ind J Pharmacol, 2001, 33, 248-259.
42. Ekroos, M.; Sjögren, T. Structural basis for ligand promiscuity in cytochrome P450 3A4. PNAS, 2006, 103, 13682-13687.
43. Williams, P. A.; Cosme, J.; Ward, A.; Angove, H. C.; Matak Vinkovic, D.; Jhoti, H. Structure of human cytochrome P450 2C9 with bound warfarin. Nature, 2003, 424, 464-468.
44. Sanz, F.; Lopez de Brinas, E.; Rodriguez, J.; Manaut, F. Theoretical study on the metabolism of caffeine by cytochrome P-450 1A2 and its inhibition. Quant. Struct.-Act. Relat., 1994, 13, 282-284.
45. Smith, D. A.; Ackland, M. J.; Jones, B. C. Properties of cytochrome P450 isoenzymes and their substrates part 2: properties of cytochrome P450 substrates. Drug Disc Tech, 1997, 2, 479-486.
46. Brøsen, K.; Skjelbo, E.; Rasmussen, B. B.; Poulsen, S.; Loft, S. Flovoxamine is a potent inhibitor of cytochrome P4501A2. Biochem. Pharmacol., 1993, 45, 1211-1214.
47. Kobayashi, K.; Nakajima, M.; Chiba, K.; Yamamoto, T.; Tani, M.; Ishizaki, T.; Kuriowa, Y. Inhibitory effects of antiarrhythmic drugs on phenacetin O-deethylation catalysed by human CYP1A2. Br. J. Clin. Pharmacol., 1998, 45, 361-368.
48. Lee, H.; Yeom, H.; Kim, Y. G.; Yoon, C. M.; Jin, C.; Choi, J. S.; Kim, B.-R.; Kim, D.-H. Structure Related Inhibition of Human Hepatic Caffeine N3-Demethylation by Naturally Occuring Flavanoids. Biochem. Pharmacol., 1998, 55, 1369-1375.
49. 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, 341-353.
50. Korhonen, L. E.; Rahnasto, M.; Mahonen, M. 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.
51. 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, 14348-14355.
52. Zhang, J.; Pan, X.; Wang, C.; Wang, F.; Li, P.; Xu, W.; He, L. Pharmacophore Modeling, 3D-QSAR Studies, and in-silico ADME Prediction of Pyrrolidine Derivatives as Neuraminidase Inhibitors. Chem Biol Drug Des, 2012, 79, 353-359.
53. Ekins, S.; Wrighton, S. A. The Role of CYP2B6 in Human Xenobiotic Metabolism. Drug Met Rev, 1999, 31, 719-754.
54. 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. Crystal structure of a cytochrome P450 2B6 genetic variant in complex with the inhibitor 4-(4-chlorophenyl) imidazole at 2.0-Å resolution. Molec Pharm, 2010, 77, 529-538.
55. Shah, M. B.; Wilderman, P. R.; Pascual, J.; Zhang, Q.; Stout, C. D.; Halpert, J. R. Conformational Adaptation of Human Cytochrome P450 2B6 and Rabbit Cytochrome P450 2B4 Revealed upon Binding Multiple Amlodipine Molecules. Biochem, 2012, 51, 7225-7238.
56. 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 Pharm Exp Thera, 1999, 288, 21-29.
57. Wang, Q.; Halpert, J. R. Combined three-dimensional quantitative structure-activity relationship analysis of cytochrome P450 2B6 substrates and protein homology modeling. Drug Met Disp, 2002, 30, 86-95.
58. Korhonen, L. E.; Turpeinen, M.; Rahnasto, M.; Wittekindt, C.; Poso, A.; Pelkonen, O.; Raunio, H.; Juvonen, R. O. New potent and selective cytochrome P450 2B6 (CYP2B6) inhibitors based on three-dimensional quantitative structure-activity relationship (3DQSAR) analysis. Brit J Pharm, 2009, 150, 932-942.
59. Ekins, S.; Iyer, M.; Krasowski, M. D.; Kharasch, E. D. Molecular characterization of CYP2B6 substrates. Curr Drug Met, 2008, 9, 363-373.
60. Miners, J. O.; Birkett, D. J. Cytochrome P4502C9: an enzyme of major importance in human drug metabolism. Br. J. Clin. Pharmacol, 1998, 45, 525-538.
61. 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., 1994, 24, 1-6.
62. 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 Met Disp, 2000, 28, 994-1002.
63. 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.
64. Afzelius, L.; Zamora, I.; Ridderström, M.; Andersson, T. B.; Karlén, A.; Masimirembwa, C. M. Competitive CYP2C9 inhibitors: enzyme inhibition studies, protein homology modeling, and three-dimensional quantitative structure-activity relationship analysis. Molec Pharm, 2001, 59, 909-919.
65. Afzelius, L.; Masimirembwa, C. M.; Karlén, A.; Andersson, T. B.; Zamora, I. Discriminant and quantitative PLS analysis of competitive CYP2C9 inhibitors versus non-inhibitors using alignment independent GRIND descriptors. J Comp-aided Molec Des, 2002, 16, 443-458.
66. 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.
67. Masimirembwa, C. M.; Ridderström, M.; Zamora, I.; Andersson, T. B. Combining pharmacophore and protein modeling to predict CYP450 inhibitors and substrates. Meth Enzym, 2002, 357, 133-144.
68. Egnell, A.-C. Generation and Evaluation of a CYP2C9 Heteroactivation Pharmacophore. J Pharm Exp Thera, 2003, 307, 878-887.
69. Wester, M. R.; Yanu, 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 ANG Resolution. J Biol Chem, 2004, 279, 35630-35637.
70. Mo, S.-L.; Zhou, Z.-W.; Yang, L.-P.; Wei, M. Q.; Zhou, S.-F. New Insights into the Structural Features and Functional Relevance of Human Cytochrome P450 2C9. Part II. Curr Drug Met, 2009, 10, 1127-1150.
71. 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 Comput Sci, 2009, 49, 853-864.
72. Rossato, G.; Ernst, B.; Smiesko, M.; Spreafico, M.; Vedani, A. Probing Small-Molecule Binding to Cytochrome P450 2D6 and 2C9: An In Silico Protocol for Generating Toxicity Alerts. Chem Med Chem, 2010, 5, 2088-2101.
73. Ridderström, M.; Zamora, I.; Fjellström, O.; Andersson, T. B. Analysis of Selective Regions in the Active Sites of Human Cytochromes P450, 2C8, 2C9, 2C18, and 2C19 Homology Models Using GRID/CPCA. J Med Chem, 2001, 44, 4072-4081.
74. Hao, M.; Zhao, Y.; Chen, P.; Huang, H.; Liu, H.; Jiang, H.; Zhang, R.; Wang, H. Structure-Activity Relationship and Substrate-Dependent Phenomena in Effects of Ginsenosides on Activities of Drug-Metabolizing P450 Enzymes. PLoS ONE, 2008, 3, e2697.
75. He, N.; Xie, H.-G.; Collins, X.; Edeki, T.; Yan, Z. Effects of Individual Ginsenosides, Ginkgolides and Flavonoids on CYP2C19 and CYP2D6 Activity in Human Liver Microsomes. Clin Exp Pharm Physiol, 2006, 33, 813-815.
76. Foti, R. S.; Rock, D. A.; Han, X.; Flowers, R. A.; Wienkers, L. C.; Wahlstrom, J. L. Ligand-Based Design of a Potent and Selective Inhibitor of Cytochrome P450 2C19. J Med Chem, 2012, 55, 1205-1214.
77. Ingelman-Sundberg, M. Implications of polymorphic cytochrome P450-dependent drug metabolism for drug development. Drug Met Disp, 2001, 29, 570-573.
78. Vermeulen, N. P. E. Prediction of drug metabolism: the case of cytochrome P450 2D6. Curr Top Med Chem, 2003, 3, 1227-1239.
79. Strobl, G. R.; von Kruedener, S.; Stoeckigt, 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.
80. 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, 1515-1524.
81. 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.
82. 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 CYP2D6 inhibitors. Pharmacogenetics, 1999, 9, 477-489.
83. Snyder, R.; Sangar, R.; Wang, J.; Ekins, S. Three-Dimensional Quantitative Structure Activity Relationship for Cyp2d6 Substrates. Quant. Struct.-Act. Relat., 2002, 21, 357-368.
84. 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.
85. Mo, S. L.; Liu, W. F.; Li, C. G.; Zhou, Z. W.; Luo, H. B.; Chew, H.; Liang, J.; Zhou, S. F. Pharmacophore, QSAR, and Binding Mode Studies of Substrates of Human Cytochrome P450 2D6 (CYP2D6) Using Molecular Docking and Virtual Mutations and an Application to Chinese Herbal Medicine Screening. Curr Pharm Biotech, 2012, 13, 1640-1704.
86. 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. Crystal structure of human cytochrome P450 2D6. J Biol Chem, 2006, 281, 7614-7622.
87. Wang, A.; Savas, U.; Hsu, M.-H.; Stout, C. D.; Johnson, E. F. Crystal Structure of Human Cytochrome P450 2D6 with Prinomastat Bound. J Biol Chem, 2012, 287, 10834-10843.
88. Mackman, R.; Guo, Z.; Guengerich, F. P.; de Montellano, P. R. O. Active site topology of human cytochrome P450 2E1. Chem Res Toxi, 1996, 9, 223-226.
89. Tan, Y.; White, S. P.; Paranawithana, R.; Yang, C. S. A hypothetical model for the active site of human cytochrome P4502E1. Xenobiotica, 1997, 27, 287-299.
90. Smith, S. V.; Koley, A. P.; Dai, R.; Robinson, R. C.; Leong, H.; Markowitz, A.; Friedman, F. K. Conformational Modulation of Human Cytochrome P450 2E1 by Ethanol and Other Substrates: A CO Flash Photolysis Study. Biochem, 2000, 39, 5731-5737.
91. Porubsky, P. R.; Meneely, K. M.; Scott, E. E. Structures of Human Cytochrome P-450 2E1: Insights into the Binding of Inhibitors and Both Small Molecular Weight and Fatty Acid Substrates. J Biol Chem, 2008, 283, 33698-33707.
92. Porubsky, P. R.; Battaile, K. P.; Scott, E. E. Human Cytochrome P450 2E1 Structures with Fatty Acid Analogs Reveal a Previously Unobserved Binding Mode. J Biol Chem, 2010, 285, 22282-22290.
93. DeVore, N. M.; Meneely, K. M.; Bart, A. G.; Stephens, E. S.; Battaile, K. P.; Scott, E. E. Structural comparison of cytochromes P450 2A6, 2A13, and 2E1 with pilocarpine. FEBS J, 2012, 279, 1621-1631.
94. 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 Met Rev, 2000, 32, 339-361.
95. Zhou, S. F. Drugs behave as substrates, inhibitors and inducers of human cytochrome P450 3A4. Curr Drug Met, 2008, 9, 310-322.
96. Hosea, N. A.; Miller, G. P.; Guengerich, F. P. Elucidation of Distinct Ligand Binding Sites for Cytochrome P450 3A4. Biochem, 2000, 39, 5929-5939.
97. 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. Biochem Biophys Res Comm, 1998, 37, 4137-4147.
98. Ekins, S.; Stresser, D. M.; Andrew Williams, J. In vitro and pharmacophore insights into CYP3A enzymes. TRENDS Pharm Sci, 2003, 24, 161-166.
99. Ekins, S.; Bravi, G.; Wikel, J. H.; Wrighton, S. A. Threedimensional-quantitative structure activity relationship analysis of cytochrome P-450 3A4 substrates. J Pharm Exp Thera, 1999, 291, 424-433.
100. 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 Pharm Exp Thera, 1999, 290, 429-438.
101. Ekins, S.; Berbaum, J.; Harrison, R. K. Generation and validation of rapid computational filters for CYP2D6 and CYP3A4. Drug Met Disp, 2003, 31, 1077-1080.
102. 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.
103. 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.
104. 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 Comput Sci, 2006, 46, 2125-2134.
105. Jones, D. R.; Ekins, S.; Li, L.; Hall, S. D. Computational Approaches That Predict Metabolic Intermediate Complex Formation with CYP3A4 (+b5). Drug Met Disp, 2007, 35, 1466-1475.
106. Sevrioukova, I. F.; Poulos, T. L. Structure and mechanism of the complex between cytochrome P4503A4 and ritonavir. PNAS, 2010, 107, 18422-18427.
107. Sevrioukova, I. F.; Poulos, T. L. Structural and mechanistic insights into the interaction of cytochrome P4503A4 with Bromoergocryptine, a type I ligand. J Biol Chem, 2012, 287, 3510-3517.
108. Sevrioukova, I. F.; Poulos, T. L. Interaction of human cytochrome P450 3A4 with ritonavir analogs. Arc Biochem Biohysics, 2012, 520, 108-116.
109. Schuster, D.; Laggner, C.; Steindl, T. M.; Palusczak, A.; Hartmann, R. W.; Langer, T. Pharmacophore Modeling and in Silico Screening for New P450 19 (Aromatase) Inhibitors. J Chem Inf Model, 2006, 46, 1301-1311.
110. Su, B.; Tian, R.; Darby, M. V.; Brueggemeier, R. W. Novel Sulfonanilide Analogs Decrease Aromatase Activity in Breast Cancer Cells: Synthesis, Biological Evaluation, and Ligand-Based Pharmacophore Identification. J Med Chem, 2008, 51, 1126-1135.
111. Neves, M. A. C.; Dinis, T. C. P.; Colombo, G.; Sáe Melo, M. L. An efficient steroid pharmacophore-based strategy to identify new aromatase inhibitors. Eur J Med Chem, 2009, 44, 4121-4127.
112. Neves, M. A. C.; Dinis, T. C. P.; Colombo, G.; Sáe Melo, M. L. Fast Three Dimensional Pharmacophore Virtual Screening of New Potent Non-Steroid Aromatase Inhibitors. J Med Chem, 2009, 52, 143-150.
113. Ghosh, D.; Griswold, J.; Erman, M.; Pangborn, W. Structural basis for Androgen Specificity and Oestrogen Synthesis in Human Aromatase. Nature Lett, 2009, 457, 219-224.
114. Muftuoglu, Y.; Mustata, G. Pharmacophore modeling strategies for the development of novel nonsteroidal inhibitors of human aromatase (CYP19). Bioorg Med Chem Lett, 2010, 20, 3050-3064.
115. Ghosh, D.; Lo, J.; Morton, D.; Valette, D.; Xi, J.; Griswold, J.; Hubbell, S.; Egbuta, C.; Jiang, W.; An, J.; Davies, H. M. L. Novel Aromatase Inhibitors by Structure-Guided Design. J Med Chem, 2012, 55, 8464-8476.
116. Yoshida, Y.; Aoyama, Y.; Noshiro, M.; Gotoh, O. Sterol 14-Demethylase P450 (CYP51) Provides a Breakthrough for the Discussion on the Evolution of Cytochrome P450 Gene Superfamily. Biochem Biophys Res Comm, 2000, 273, 799-804.
117. Tafi, A.; Anastassopoulou, J.; Theophanides, T.; Botta, M.; Corelli, F.; Massa, S.; Artico, M.; Costi, R.; Di Santo, R.; Ragno, R. Molecular Modeling of Azole Antifungal Agents Active against Candida albicans. 1. A Comparative Molecular Field Analysis Study. J Med Chem, 1996, 39, 1227-1235.
118. Tafi, A.; Costi, R.; Botta, M.; Di Santo, R.; Corelli, F.; Massa, S.; Ciacci, A.; Manetti, F.; Artico, M. Antifungal Agents. 10. New Derivatives of 1-[(Aryl)[4-aryl-1 H-pyrrol-3-yl]methyl]-1 H-imidazole, Synthesis, Anti-Candida Activity, and Quantitative Structure-Analysis Relationship Studies. J Med Chem, 2002, 45, 2720-2732.
119. Ekins, S.; Mankowski, D. C.; Hoover, D. J.; Lawton, M. P.; Treadway, J. L.; Harwood, H. J. Three-Dimensional Quantitative Structure-Activity Relationship Analysis of Human CYP51 Inhibitors. Drug Met Disp, 2006, 35, 493-500.
120. Liu, J.; Pan, D.; Tseng, Y.; Hopfinger, A. J. 4D-QSAR Analysis of a Series of Antifungal P450 Inhibitors and 3D-Pharmacophore Comparisons as a Function of Alignment. J Chem Inf Comput Sci, 2003, 43, 2170-2179.
121. Podust, L. M.; Poulos, T. L.; Waterman, M. R. Crystal structure of cytochrome P450 14'-sterol demethylase (CYP51) from Mycobacterium tuberculosis in complex with azole inhibitors. PNAS, 2001, 98, 3068-3073.
122. Podust, L. M.; Yermalitskaya, L. V.; Lepesheva, G. I.; Podust, V. N.; Dalmasso, E. A.; Waterman, M. R. Estriol Bound and Ligandfree Structures of Sterol 14'-Demethylase. Structure, 2004, 12, 1937-1945.
123. Podust, L. M.; von Kries, J. P.; Eddine, A. N.; Kim, Y.; Yermalitskaya, L. V.; Kuehne, R.; Ouellet, H.; Warrier, T.; Altekoster, M.; Lee, J.-S.; Rademann, J.; Oschkinat, H.; Kaufmann, S. H. E.; Waterman, M. R. Small-Molecule Scaffolds for CYP51 Inhibitors Identified by High-Throughput Screening and Defined by X-Ray Crystallography. Antimic Agents Chem, 2007, 51, 3915-3923.
124. Eddine, A. N.; von Kries, J. P.; Podust, M. V.; Warrier, T.; Kaufmann, S. H. E.; Podust, L. M. X-ray Structure of 4,4'-Dihydroxybenzophenone Mimicking Sterol Substrate in the Active Site of Sterol 14-Demethylase (CYP51). J Biol Chem, 2008, 283, 15152-15159.
125. Bertilsson, G.; Heidrich, J.; Svensson, K.; Asman, M.; Jendeberg, L.; Sydow-Bäckman, M.; Ohlsson, R.; Postlind, H.; Blomquist, P.; Berkenstam, A. Identification of a human nuclear receptor defines a new signaling pathway for CYP3A induction. PNAS, 1998, 95, 12208-12213.
126. Ekins, S.; Erickson, J. A. A pharmacophore for human pregnane X receptor ligands. Drug Met Disp, 2002, 30, 96-99.
127. Yasuda, K.; Ranade, A.; Venkataramanan, R.; Strom, S.; Chupka, J.; Ekins, S.; Schuetz, E.; Bachmann, K. A Comprehensive in Vitro and in Silico Analysis of Antibiotics That Activate Pregnane X Receptor and Induce CYP3A4 in Liver and Intestine. Drug Met Disp, 2008, 36, 1689-1697.
128. Ekins, S.; Obach, R. S. Three-dimensional quantitative structure activity relationship computational approaches for prediction of human in vitro intrinsic clearance. J Pharm Exp Thera, 2000, 295, 463-473.
129. Ekins, S.; Ring, B. J.; Bravi, G.; Wikel, J. H.; Wrighton, S. A. Predicting Drug-Drug Interactions in Silico Using Pharmacophore Models: A Paradigm for the Next Millenium. In Pharmacophore Perception, Development, and Use in Drug Design; Güner, O. F. Ed.; International University Line: La Jolla, California, 2000; pp. 271-299.
130. Ekins, S. Predicting undesirable drug interactions with promiscuous proteins in silico. DDT, 2004, 9, 276-285.
131. Güner, O. F.; Henry, D. R. Metrics for Analyzing Hit Lists and Pharmacophores. In Pharmacophore Perception, Development, and Use in Drug Design; Güner, O. F. Ed.; International University Line: La Jolla, California, 2000; pp. 193-211.
132. Güner, O. F.; Waldman, M.; Hoffmann, R.; Kim, J.-H. Strategies in Database Mining and Pharmacophore Development. In Pharmacophore Perception, Development, and Use in Drug Design; Güner, O. F. Ed.; International University Line: La Jolla, California, 2000; pp. 213-232.
133. Raymond, J. W.; Willett, P. Effectiveness of graph-based and fingerprint-based similarity measures for virtual screening of 2D chemical structure databases. J Comp-aided Molec Des, 2002, 16, 59-71.
134. Edgar, S. J.; Holliday, J. D.; Willett, P. Effectiveness of retrieval in similarity searches of chemical databases: a review of performance measures. J Molec Graph Model, 2000, 18, 343-357.