Journal of Medicinal Chemistry · 2007 · 38 citations · 21 references
MedicineBiochemistryPharmacologyDrug DiscoveryDrug MetabolismMetabolismCytochrome P450 EnzymesCytochrome P450 InteractionsDrug-metabolizing EnzymesMetabolite IdentificationMolecular DockingXenobiotic MetabolismCytochrome P450 2C9Cytochrome P450 Enzyme InhibitionCytochrome P450 Inhibition PredictionCytochrome P450 Metabolite IdentificationCytochrome P450 OxidationCytochrome P450 Structure-function RelationshipsDocking Pose EvaluationEnzyme-substrate Interactions
The cytochrome P450 (CYP) family is composed of monooxygenases, which mediate the metabolism of xenobiotics and endogenous compounds. The characterization of the interactions between these enzymes and candidate drugs is an important part of the drug discovery process. CYP2C9, one isoform of the CYPs, mediates the oxidation of several important drugs. The aim of this work is to investigate the possibility to study inhibition and substrate interactions with CYP2C9, using docking and the site of metabolism predictions. The model compounds used for the study were the COX-2 inhibitor celecoxib and a series of 13 analogues known to be metabolized by CYP2C9. The results obtained using the two methods gave valuable information about important interactions of inhibitors and substrates with CYP2C9. The two methods could be used to predict the site of metabolism and to determine the productive docking pose for each compound. These predictions were verified by metabolite identification using LC/MS/MS after incubation with recombinant CYP2C9.
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Crystal structure of human cytochrome P450 2C9 with bound warfarin
Pamela A. Williams, José Cosme, Alison Ward et al. · Nature · 2003 · 817 citations
Mammalian Microsomal Cytochrome P450 Monooxygenase
Pamela A. Williams, José Cosme, Vandana Sridhar et al. · Molecular Cell · 2000 · 694 citations · Full text