title: Substrate selectivity of drug-metabolizing cytochrome P450s predicted from crystal structures and in silico modeling.
abstract: Enormous efforts toward predicting the metabolic fate of a drug have been driven by the high attrition rate in drug development. To accelerate such efforts, it is critical to elucidate the molecular mechanisms of drug recognition by drug-metabolizing enzymes. Therefore, it is not surprising that an increasing number of crystal structures have been determined (by X-ray crystallography) and numerous insightful in silico (computational) models have been established for the most important metabolic enzymes, cytochrome P450s (CYPs). In this review, we provide a detailed analysis of the available crystal structures for CYPs to reveal the structural features and protein flexibility determining substrate selectivity. The ligand-based in silico models (including pharmacophore and molecular field analysis models) are also discussed, with a focus on their ability to characterize the structural features of the substrates for various CYP isoforms.
authors.affiliation: Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Texas 77030, USA.
authors.forename: Dong
authors.initials: D
authors.lastname: Dong
authors.forename: Baojian
authors.initials: B
authors.lastname: Wu
mesh_terms: D000595:Amino Acid Sequence; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D003577:Cytochrome P-450 Enzyme System / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007527:Isoenzymes / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D008024:Ligands; D008958:Models, Molecular; D008962:Models, Theoretical; D008969:Molecular Sequence Data; D015394:Molecular Structure; D004364:Pharmaceutical Preparations / Q000737:chemistry* / Q000378:metabolism*; D011487:Protein Conformation; D016415:Sequence Alignment; D013379:Substrate Specificity
chemical_list: D007527:Isoenzymes; D008024:Ligands; D004364:Pharmaceutical Preparations; D003577:Cytochrome P-450 Enzyme System