title: Empirical regioselectivity models for human cytochromes P450 3A4, 2D6, and 2C9.
abstract: Cytochromes P450 3A4, 2D6, and 2C9 metabolize a large fraction of drugs. Knowing where these enzymes will preferentially oxidize a molecule, the regioselectivity, allows medicinal chemists to plan how best to block its metabolism. We present QSAR-based regioselectivity models for these enzymes calibrated against compiled literature data of drugs and drug-like compounds. These models are purely empirical and use only the structures of the substrates, in contrast to those models that simulate a specific mechanism like hydrogen radical abstraction, and/or use explicit models of active sites. Our most predictive models use three substructure descriptors and two physical property descriptors. Descriptor importances from the random forest QSAR method show that other factors than the immediate chemical environment and the accessibility of the hydrogen affect regioselectivity in all three isoforms. The cross-validated predictions of the models are compared to predictions from our earlier mechanistic model (Singh et al. J. Med. Chem. 2003, 46, 1330-1336) and predictions from MetaSite (Cruciani et al. J. Med. Chem. 2005, 48, 6970-6979).
authors.affiliation: Molecular Systems Department, RY50S-100, Merck Research Laboratories, Rahway, New Jersey 07065, USA. sheridan@merck.com
authors.forename: Robert P
authors.initials: RP
authors.lastname: Sheridan
authors.forename: Kenneth R
authors.initials: KR
authors.lastname: Korzekwa
authors.forename: Rhonda A
authors.initials: RA
authors.lastname: Torres
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Walker
mesh_terms: D003577:Cytochrome P-450 Enzyme System / Q000187:drug effects*; D036262:Empirical Research; D006801:Humans; D006859:Hydrogen / Q000737:chemistry; D008956:Models, Chemical; D021281:Quantitative Structure-Activity Relationship; D012372:ROC Curve
chemical_list: D006859:Hydrogen; D003577:Cytochrome P-450 Enzyme System