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Xenobiotica
the fate of foreign compounds in biological systems
Volume 28, 1998 - Issue 3
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Research Article

Molecular modelling of human CYP2C subfamily enzymes CYP2C9 and CYP2C19: rationalization of substrate specificity and site-directed mutagenesis experiments in the CYP2C subfamily

D. F. V. LEWIS Molecular Toxicology Group, School of Biological Sciences, University of Surrey, Guildford GU2 5XH, UK OE Glaxo Wellcome Research and Development Ltd, Park Road, Ware SG12 0DP, UK Servier Research and Development, Fulmer Hall, Windmill Road, Fulmer, Slough SL3 6HH, UK
,
M. DICKINS Molecular Toxicology Group, School of Biological Sciences, University of Surrey, Guildford GU2 5XH, UK OE Glaxo Wellcome Research and Development Ltd, Park Road, Ware SG12 0DP, UK Servier Research and Development, Fulmer Hall, Windmill Road, Fulmer, Slough SL3 6HH, UK
,
R. J. WEAVER Molecular Toxicology Group, School of Biological Sciences, University of Surrey, Guildford GU2 5XH, UK OE Glaxo Wellcome Research and Development Ltd, Park Road, Ware SG12 0DP, UK Servier Research and Development, Fulmer Hall, Windmill Road, Fulmer, Slough SL3 6HH, UK
,
P. J. EDDERSHAW Molecular Toxicology Group, School of Biological Sciences, University of Surrey, Guildford GU2 5XH, UK OE Glaxo Wellcome Research and Development Ltd, Park Road, Ware SG12 0DP, UK Servier Research and Development, Fulmer Hall, Windmill Road, Fulmer, Slough SL3 6HH, UK
,
P. S. GOLDFARB Molecular Toxicology Group, School of Biological Sciences, University of Surrey, Guildford GU2 5XH, UK OE Glaxo Wellcome Research and Development Ltd, Park Road, Ware SG12 0DP, UK Servier Research and Development, Fulmer Hall, Windmill Road, Fulmer, Slough SL3 6HH, UK
&
M. H. TARBIT Molecular Toxicology Group, School of Biological Sciences, University of Surrey, Guildford GU2 5XH, UK OE Glaxo Wellcome Research and Development Ltd, Park Road, Ware SG12 0DP, UK Servier Research and Development, Fulmer Hall, Windmill Road, Fulmer, Slough SL3 6HH, UK
Pages 235-268 | Published online: 22 Sep 2008

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Khaled Abass, Miia Turpeinen & Olavi Pelkonen. (2009) An evaluation of the cytochrome P450 inhibition potential of selected pesticides in human hepatic microsomes. Journal of Environmental Science and Health, Part B 44:6, pages 553-563.
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Sean Ekins, Sergey Andreyev, Andy Ryabov, Eugene Kirillov, Eugene A Rakhmatulin, Andrej Bugrim & Tatiana Nikolskaya. (2005) Computational prediction of human drug metabolism. Expert Opinion on Drug Metabolism & Toxicology 1:2, pages 303-324.
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David F. V. Lewis, Sandeep Modi & Maurice Dickins. (2002) Structure–activity relationship for human cytochrome P450 substrates and inhibitors. Drug Metabolism Reviews 34:1-2, pages 69-82.
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David F. V. Lewis. (2002) Molecular modeling of human cytochrome P450–substrate interactions. Drug Metabolism Reviews 34:1-2, pages 55-67.
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David F.V. Lewis & Maurice Dickins. (2001) Quantitative Structure-Activity Relationships (QSARs) Within Series of Inhibitors for Mammalian Cytochromes P450 (CYPs). Journal of Enzyme Inhibition 16:4, pages 321-330.
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S. A. Roberts. (2001) High-throughput screening approaches for investigating drug metabolism and pharmacokinetics. Xenobiotica 31:8-9, pages 557-589.
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Avanthika Venkatachalam, Abhinav Parashar & Kelath Murali Manoj. (2016) Functioning of drug-metabolizing microsomal cytochrome P450s: In silico probing of proteins suggests that the distal heme ‘active site’ pocket plays a relatively ‘passive role’ in some enzyme-substrate interactions. In Silico Pharmacology 4:1.
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Manish B. Shah, P. Ross Wilderman, Jaime Pascual, Qinghai Zhang, C. David Stout & James R. Halpert. (2012) Conformational Adaptation of Human Cytochrome P450 2B6 and Rabbit Cytochrome P450 2B4 Revealed upon Binding Multiple Amlodipine Molecules. Biochemistry 51:37, pages 7225-7238.
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Ruifeng Liu, Jin Liu, Greg Tawa & Anders Wallqvist. (2012) 2D SMARTCyp Reactivity-Based Site of Metabolism Prediction for Major Drug-Metabolizing Cytochrome P450 Enzymes. Journal of Chemical Information and Modeling 52:6, pages 1698-1712.
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Chandramouli Malleda, Navjeet Ahalawat, Mahesh Gokara & Rajagopal Subramanyam. (2011) Molecular dynamics simulation studies of betulinic acid with human serum albumin. Journal of Molecular Modeling 18:6, pages 2589-2597.
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Rajagopal Subramanyam, Anilkishor Gollapudi, Persis Bonigala, Madhurarekha Chinnaboina & Damu G. Amooru. (2009) Betulinic acid binding to human serum albumin: A study of protein conformation and binding affinity. Journal of Photochemistry and Photobiology B: Biology 94:1, pages 8-12.
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Praveen Rajendran, Manu Jaggi, Manoj K. Singh, Rama Mukherjee & Anand C. Burman. (2007) Pharmacological evaluation of C-3 modified Betulinic acid derivatives with potent anticancer activity. Investigational New Drugs 26:1, pages 25-34.
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Maori Mitsuda, Masahiko Iwasaki & Satoru Asahi. (2006) Cynomolgus Monkey Cytochrome P450 2C43: cDNA Cloning, Heterologous Expression, Purification and Characterization. The Journal of Biochemistry 139:5, pages 865-872.
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Peter Hlavica. (2006) Functional interaction of nitrogenous organic bases with cytochrome P450: A critical assessment and update of substrate features and predicted key active-site elements steering the access, binding, and orientation of amines. Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics 1764:4, pages 645-670.
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Michael Murray. 2005. Modern Biopharmaceuticals. Modern Biopharmaceuticals 1603 1636 .
Carol A. Kemp, Jean-Didier Maréchal & Michael J. Sutcliffe. (2005) Progress in cytochrome P450 active site modeling. Archives of Biochemistry and Biophysics 433:2, pages 361-368.
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Akifumi Oda, Noriyuki Yamaotsu & Shuichi Hirono. (2004) Studies of Binding Modes of (S)-Mephenytoin to Wild Types and Mutants of Cytochrome P450 2C19 and 2C9 Using Homology Modeling and Computational Docking. Pharmaceutical Research 21:12, pages 2270-2278.
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Lovisa Afzelius, Florian Raubacher, Anders Karlén, Flemming Steen Jørgensen, Tommy B. Andersson, Collen M. Masimirembwa & Ismael Zamora. (2004) STRUCTURAL ANALYSIS OF CYP2C9 AND CYP2C5 AND AN EVALUATION OF COMMONLY USED MOLECULAR MODELING TECHNIQUES. Drug Metabolism and Disposition 32:11, pages 1218-1229.
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Hisashi Suzuki, M.Byron Kneller, Dan A Rock, Jeffrey P Jones, William F Trager & Allan E Rettie. (2004) Active-site characteristics of CYP2C19 and CYP2C9 probed with hydantoin and barbiturate inhibitors. Archives of Biochemistry and Biophysics 429:1, pages 1-15.
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Carwyn Davies, Katey Witham, Justin R. Scott, Andrew Pearson, James J. DeVoss, Sandra E. Graham & Elizabeth M. J. Gillam. (2004) ASSESSMENT OF ARGININE 97 AND LYSINE 72 AS DETERMINANTS OF SUBSTRATE SPECIFICITY IN CYTOCHROME P450 2C9 (CYP2C9). Drug Metabolism and Disposition 32:4, pages 431-436.
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Khawja A. Usmani, Edward D. Karoly, Ernest Hodgson & Randy L. Rose. (2004) IN VITRO SULFOXIDATION OF THIOETHER COMPOUNDS BY HUMAN CYTOCHROME P450 AND FLAVIN-CONTAINING MONOOXYGENASE ISOFORMS WITH PARTICULAR REFERENCE TO THE CYP2C SUBFAMILY. Drug Metabolism and Disposition 32:3, pages 333-339.
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David F.V. Lewis. (2004) Quantitative structure–activity relationships (QSARs) for substrates of human cytochromes P450 CYP2 family enzymes. Toxicology in Vitro 18:1, pages 89-97.
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Rory P. Remmel, Brenda C. Crews, Kevin R. Kozak, Amit S. Kalgutkar & Lawrence J. Marnett. (2004) STUDIES ON THE METABOLISM OF THE NOVEL, SELECTIVE CYCLOOXYGENASE-2 INHIBITOR INDOMETHACIN PHENETHYLAMIDE IN RAT, MOUSE, AND HUMAN LIVER MICROSOMES: IDENTIFICATION OF ACTIVE METABOLITES. Drug Metabolism and Disposition 32:1, pages 113-122.
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Robert H. Cichewicz & Samir A. Kouzi. (2003) Chemistry, biological activity, and chemotherapeutic potential of betulinic acid for the prevention and treatment of cancer and HIV infection. Medicinal Research Reviews 24:1, pages 90-114.
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David F. V. Lewis. (2003) Quantitative structure–activity relationships (QSARs) within the cytochrome P450 system: QSARs describing substrate binding, inhibition and induction of P450s. InflammoPharmacology 11:1, pages 43-73.
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Armelle Melet, Nadine Assrir, Pascale Jean, Maria Pilar Lopez-Garcia, Cristina Marques-Soares, Maryse Jaouen, Patrick M Dansette, Marie-Agnès Sari & Daniel Mansuy. (2003) 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. Archives of Biochemistry and Biophysics 409:1, pages 80-91.
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David F.V. Lewis. (2002) Modelling human cytochromes P450 involved in drug metabolism from the CYP2C5 crystallographic template. Journal of Inorganic Biochemistry 91:4, pages 502-514.
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Stewart B Kirton, Carol A Baxter & Michael J Sutcliffe. (2002) Comparative modelling of cytochromes P450. Advanced Drug Delivery Reviews 54:3, pages 385-406.
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Zeruesenay Desta, Xiaojiong Zhao, Jae-Gook Shin & David A. Flockhart. (2002) Clinical Significance of the Cytochrome P450 2C19 Genetic Polymorphism. Clinical Pharmacokinetics 41:12, pages 913-958.
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D. F. V. Lewis. 2002. Pharmacokinetic Challenges in Drug Discovery. Pharmacokinetic Challenges in Drug Discovery 235 248 .
Nguyêt-Thanh Ha-Duong, Cristina Marques-Soares, Sylvie Dijols, Marie-Agnès Sari, Patrick M. Dansette & Daniel Mansuy. (2001) Interaction of New Sulfaphenazole Derivatives with Human Liver Cytochrome P450 2Cs: Structural Determinants Required for Selective Recognition by CYP 2C9 and for Inhibition of Human CYP 2Cs. Archives of Biochemistry and Biophysics 394:2, pages 189-200.
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Cuyue Tang, Magang Shou, Thomas H. Rushmore, Qin Mei, Punam Sandhu, Eric J. Woolf, Mark J. Rose, Alyssa Gelmann, Howard E. Greenberg, Inge De Lepeleire, Anne Van Hecken, Paul J. De Schepper, David L. Ebel, Jules I. Schwartz & A. David Rodrigues. (2001) In-vitro metabolism of celecoxib, a cyclooxygenase-2 inhibitor, by allelic variant forms of human liver microsomal cytochrome P450 2C9: correlation with CYP2C9 genotype and in-vivo pharmacokinetics. Pharmacogenetics 11:3, pages 223-235.
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Marianne Ridderström, Collen Masimirembwa, Susanne Trump-Kallmeyer, Maria Ahlefelt, Charlotta Otter & Tommy B. Andersson. (2000) Arginines 97 and 108 in CYP2C9 Are Important Determinants of the Catalytic Function. Biochemical and Biophysical Research Communications 270:3, pages 983-987.
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D.F.V. Lewis. (2000) Modelling Human Cytochromes P450 for Evaluating Drug Metabolism: An Update. Drug Metabolism and Drug Interactions 16:4.
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