title: Progress in cytochrome P450 active site modeling.
abstract: Models capable of predicting the possible involvement of cytochromes P450 in the metabolism of drugs or drug candidates are important tools in drug discovery and development. Ideally, functional information would be obtained from crystal structures of all the cytochromes P450 of interest. Initially, only crystal structures of distantly related bacterial cytochromes P450 were available-comparative modeling techniques were used to bridge the gap and produce structural models of human cytochromes P450, and thereby obtain some useful functional information. A significant step forward in the reliability of these models came four years ago with the first crystal structure of a mammalian cytochrome P450, rabbit CYP2C5, followed by the structures of two human enzymes, CYP2C8 and CYP2C9, and a second rabbit enzyme, CYP2B4. The evolution of a CYP2D6 model, leading to the validation of the model as an in silico tool for predicting binding and metabolism, is presented as a case study.
authors.affiliation: Department of Biochemistry, University of Leicester, Leicester LE1 7RH, UK.
authors.forename: Carol A
authors.initials: CA
authors.lastname: Kemp
authors.forename: Jean-Didier
authors.initials: JD
authors.lastname: Maréchal
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Sutcliffe
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000737:chemistry / Q000378:metabolism; D001665:Binding Sites; D065727:Cytochrome P-450 CYP2C8; D065729:Cytochrome P-450 CYP2C9; D019389:Cytochrome P-450 CYP2D6 / Q000737:chemistry / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D000072467:Cytochrome P450 Family 2; D016208:Databases, Factual; D006801:Humans; D021621:Imaging, Three-Dimensional; D007527:Isoenzymes / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D008958:Models, Molecular; D008961:Models, Structural; D010802:Phylogeny; D011485:Protein Binding; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D011817:Rabbits; D015203:Reproducibility of Results; D017386:Sequence Homology, Amino Acid; D013379:Substrate Specificity
chemical_list: D007527:Isoenzymes; D003577:Cytochrome P-450 Enzyme System; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; C450259:CYP2C8 protein, human; D065727:Cytochrome P-450 CYP2C8; D019389:Cytochrome P-450 CYP2D6; D000072467:Cytochrome P450 Family 2; C465241:cytochrome P-450 CYP2B4 (rabbit)