title: Development of a combined protein and pharmacophore model for cytochrome P450 2C9.
abstract: A combined protein and pharmacophore model for cytochrome P450 2C9 (CYP2C9) has been derived using various computational chemistry techniques. A combination of pharmacophore modeling (using 31 metabolic pathways for 27 substrates), protein modeling (using the rabbit CYP2C5/3 crystal structure), and molecular orbital calculations was used to derive a model that incorporated steric, electronic, and chemical stability properties. The initial pharmacophore model (based on a subset of 17 metabolic pathways for 16 substrates) and the protein model used to construct the combined model were derived independently and showed a large degree of complementarity. The combined model is in agreement with experimental results concerning the substrates used to derive the model and with site-directed mutagenesis data available for CYP2C9. The model has been successfully used to predict the metabolism of substrates not used to construct the model, of which four examples are discussed in detail. The model has also been successful in explaining the differences in substrate specificity between CYP2C9 and CYP2C19.
authors: Department of Molecular Informatics, Structure & Design, Pfizer Global Research & Development, Sandwich Laboratories, Ramsgate Road, Sandwich, Kent CT13 9NJ, U.K. degroot@sandwich.pfizer.com
authors: Marcel J
authors: MJ
authors: de Groot
authors: Alexander A
authors: AA
authors: Alex
authors: Barry C
authors: BC
authors: Jones
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases; D001665:Binding Sites; D018360:Crystallography, X-Ray; D003577:Cytochrome P-450 Enzyme System / Q000737:chemistry*; D000072467:Cytochrome P450 Family 2; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D010084:Oxidation-Reduction; D021281:Quantitative Structure-Activity Relationship; D011789:Quantum Theory; D011817:Rabbits; D016415:Sequence Alignment; D039181:Steroid 16-alpha-Hydroxylase; D013255:Steroid 21-Hydroxylase / Q000737:chemistry; D013250:Steroid Hydroxylases / Q000737:chemistry*
chemical_list: D003577:Cytochrome P-450 Enzyme System; D013250:Steroid Hydroxylases; D001189:Aryl Hydrocarbon Hydroxylases; C065407:CYP2C5 protein, Oryctolagus cuniculus; D000072467:Cytochrome P450 Family 2; D039181:Steroid 16-alpha-Hydroxylase; D013255:Steroid 21-Hydroxylase