title: Predicting drug metabolism: a site of metabolism prediction tool applied to the cytochrome P450 2C9.
abstract: The aim of the present study is to develop a method for predicting the site at which molecules will be metabolized by CYP 2C9 (cytochrome P450 2C9) using a previously reported protein homology model of the enzyme. Such a method would be of great help in designing new compounds with a better pharmacokinetic profile, or in designing prodrugs where the compound needs to be metabolized in order to become active. The methodology is based on a comparison between alignment-independent descriptors derived from GRID Molecular Interaction Fields for the CYP 2C9 active site, and a distance-based representation of the substrate. The predicted site of metabolism is reported as a ranking list of all the hydrogen atoms of each substrate molecule. Eighty-seven CYP 2C9-catalyzed oxidative reactions reported in the literature have been analyzed. In more than 90% of these cases, the hydrogen atom ranked at the first, second, or third position was the experimentally reported site of oxidation.
authors.affiliation: Drug Metabolism, Pharmacokinetic and Bioanalytical Chemistry, AstraZeneca R&D Mölndal, Sweden. ismael.zamora@telefonica.net
authors.forename: Ismael
authors.initials: I
authors.lastname: Zamora
authors.forename: Lovisa
authors.initials: L
authors.lastname: Afzelius
authors.forename: Gabriele
authors.initials: G
authors.lastname: Cruciani
mesh_terms: D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000737:chemistry* / Q000378:metabolism; D065729:Cytochrome P-450 CYP2C9; D006801:Humans; D006859:Hydrogen / Q000737:chemistry; D008958:Models, Molecular; D008968:Molecular Conformation; D010084:Oxidation-Reduction; D004364:Pharmaceutical Preparations / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding; D021281:Quantitative Structure-Activity Relationship
chemical_list: D004364:Pharmaceutical Preparations; D006859:Hydrogen; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases