title: Structure-based CoMFA as a predictive model - CYP2C9 inhibitors as a test case.
abstract: In this study, we tried to establish a general scheme to create a model that could predict the affinity of small compounds to their target proteins. This scheme consists of a search for ligand-binding sites on a protein, a generation of bound conformations (poses) of ligands in each of the sites by docking, identifications of the correct poses of each ligand by consensus scoring and MM-PBSA analysis, and a construction of a CoMFA model with the obtained poses to predict the affinity of the ligands. By using a crystal structure of CYP 2C9 and the twenty known CYP inhibitors as a test case, we obtained a CoMFA model with a good statistics, which suggested that the classification of the binding sites as well as the predicted bound poses of the ligands should be reasonable enough. The scheme described here would give a method to predict the affinity of small compounds with a reasonable accuracy, which is expected to heighten the value of computational chemistry in the drug design process.
authors.affiliation: Discovery Research Laboratories, Shionogi & Co., Ltd. 12-4, Sagisu 5-Chome, Fukushima-ku, Osaka 553-0002, Japan. kazuya.yasuo@shionogi.co.jp
authors.forename: Kazuya
authors.initials: K
authors.lastname: Yasuo
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Yamaotsu
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Gouda
authors.forename: Hideki
authors.initials: H
authors.lastname: Tsujishita
authors.forename: Shuichi
authors.initials: S
authors.lastname: Hirono
mesh_terms: D000465:Algorithms; D000595:Amino Acid Sequence; D000925:Anticoagulants / Q000378:metabolism; D001189:Aryl Hydrocarbon Hydroxylases / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D001665:Binding Sites; D019295:Computational Biology; D018360:Crystallography, X-Ray; D065729:Cytochrome P-450 CYP2C9; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D005544:Forecasting; D006418:Heme / Q000737:chemistry; D008024:Ligands; D008958:Models, Molecular; D008969:Molecular Sequence Data; D021281:Quantitative Structure-Activity Relationship; D013329:Structure-Activity Relationship; D014859:Warfarin / Q000378:metabolism
chemical_list: D000925:Anticoagulants; D004791:Enzyme Inhibitors; D008024:Ligands; D006418:Heme; D014859:Warfarin; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases