title: Mechanism of the decrease in catalytic activity of human cytochrome P450 2C9 polymorphic variants investigated by computational analysis.
abstract: Cytochrome P450 (CYP) is deeply involved in the metabolism of chemicals including pharmaceuticals. Therefore, polymorphisms of this enzyme have been widely studied to avoid unfavorable side effects of drugs in chemotherapy. In this work, we performed computational analysis of the mechanism of the decrease in enzymatic activity for three typical polymorphisms in CYP 2C9 species: *2, *3, and *5. Based on the equilibrated structure obtained by molecular dynamics simulation, the volume of the binding pocket and the fluctuation of amino residues responsible for substrate holding were compared between the wild type and the three variants. Further docking simulation was carried out to evaluate the appropriateness of the binding pocket to accommodate substrate chemicals. Every polymorphic variant was suggested to be inferior to the wild type in enzymatic ability from the structural viewpoint. F-G helices were obviously displaced outward in CYP2C9*2. Expansion of the binding pocket, especially the space near F' helix, was remarkable in CYP2C9*3. Disappearance of the hydrogen bond between K helix and β4 loop was observed in CYP2C9*5. The reduction of catalytic activity of those variants can be explained from the deformation of the binding pocket and the consequent change in binding mode of substrate chemicals. The computational approach is effective for predicting the enzymatic activity of polymorphic variants of CYP. This prediction will be helpful for advanced drug design because calculations forecast unexpected change in drug efficacy for individuals.
authors.affiliation: Department of Physical Chemistry, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba 263-8522, Japan.
authors.forename: Eri
authors.initials: E
authors.lastname: Sano
authors.forename: Weihua
authors.initials: W
authors.lastname: Li
authors.forename: Hitomi
authors.initials: H
authors.lastname: Yuki
authors.forename: Xinli
authors.initials: X
authors.lastname: Liu
authors.forename: Tomomi
authors.initials: T
authors.lastname: Furihata
authors.forename: Kaoru
authors.initials: K
authors.lastname: Kobayashi
authors.forename: Kan
authors.initials: K
authors.lastname: Chiba
authors.forename: Saburo
authors.initials: S
authors.lastname: Neya
authors.forename: Tyuji
authors.initials: T
authors.lastname: Hoshino
mesh_terms: D000465:Algorithms; D001189:Aryl Hydrocarbon Hydroxylases / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D001665:Binding Sites / Q000235:genetics; D055162:Biocatalysis; D065729:Cytochrome P-450 CYP2C9; D014644:Genetic Variation; D006801:Humans; D056004:Molecular Dynamics Simulation; D011110:Polymorphism, Genetic; D017433:Protein Structure, Secondary; D013329:Structure-Activity Relationship; D013379:Substrate Specificity / Q000235:genetics
chemical_list: C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases