title: In silico modeling of p450 substrates, inhibitors, activators, and inducers.
abstract: Cytochrome P450 enzymes are the predominant mediators of phase I metabolism of exogenous small molecules. As a result of their extensive role in metabolism of xenobiotics, drug compounds, and endogenous compounds, as well as their wide tissue distribution, significant drug discovery resources are spent to avoid interacting with this class of enzymes. Here we review historical and recent in silico modeling of 7 cytochrome P450 enzymes of particular interest, specifically CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. For each we provide a brief biological background including known inhibitors, substrates, and inducers, as well as details of computational modeling efforts and advances in structural biology. We also provide similar details for 3 nuclear receptors known to regulate gene expression of these enzyme families.
authors.affiliation: Array BioPharma, Inc, Boulder, Colorado 80301, USA. Kirk.DeLisle@arraybiopharma.com
authors.forename: Robert Kirk
authors.initials: RK
authors.lastname: DeLisle
authors.forename: Jennifer
authors.initials: J
authors.lastname: Otten
authors.forename: Susan
authors.initials: S
authors.lastname: Rhodes
mesh_terms: D019295:Computational Biology; D003198:Computer Simulation; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000737:chemistry / Q000378:metabolism; D055808:Drug Discovery; D008954:Models, Biological; D004364:Pharmaceutical Preparations / Q000737:chemistry / Q000378:metabolism*
chemical_list: D065607:Cytochrome P-450 Enzyme Inhibitors; D004364:Pharmaceutical Preparations; D003577:Cytochrome P-450 Enzyme System