title: Distal effect of amino acid substitutions in CYP2C9 polymorphic variants causes differences in interatomic interactions against (S)-warfarin.
abstract: Cytochrome P450 2C9 (CYP2C9) is crucial in excretion of commonly prescribed drugs. However, changes in metabolic activity caused by CYP2C9 polymorphisms inevitably result in adverse drug effects. CYP2C9*2 and *3 are prevalent in Caucasian populations whereas CYP2C9*13 is remarkable in Asian populations. Single amino acid substitutions caused by these mutations are located outside catalytic cavity but affect kinetic activities of mutants compared to wild-type enzyme. To relate distal effects of these mutations and defective drug metabolisms, simulations of CYP2C9 binding to anti-coagulant (S)-warfarin were performed as a system model. Representative (S)-warfarin-bound forms of wild-type and mutants were sorted and assessed through knowledge-based scoring function. Interatomic interactions towards (S)-warfarin were predicted to be less favorable in mutant structures in correlation with larger distance between hydroxylation site of (S)-warfarin and reactive oxyferryl heme than wild-type structure. Using computational approach could delineate complication of CYP polymorphism in management of drug therapy.
authors.affiliation: Department of Biochemistry, Faculty of Science, Mahidol University, Bangkok, Thailand ; Genomics Institute, National Center for Genetic Engineering and Biotechnology, Pathumtani, Thailand ; Department of Microbiology, University of Washington, Seattle, Washington, United States of America.
authors.forename: Panida
authors.initials: P
authors.lastname: Lertkiatmongkol
authors.forename: Anunchai
authors.initials: A
authors.lastname: Assawamakin
authors.forename: George
authors.initials: G
authors.lastname: White
authors.forename: Gaurav
authors.initials: G
authors.lastname: Chopra
authors.forename: Pornpimol
authors.initials: P
authors.lastname: Rongnoparut
authors.forename: Ram
authors.initials: R
authors.lastname: Samudrala
authors.forename: Sissades
authors.initials: S
authors.lastname: Tongsima
mesh_terms: D019943:Amino Acid Substitution; D003577:Cytochrome P-450 Enzyme System / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D011110:Polymorphism, Genetic; D011485:Protein Binding; D011487:Protein Conformation; D013379:Substrate Specificity; D014859:Warfarin / Q000378:metabolism*
chemical_list: D014859:Warfarin; D003577:Cytochrome P-450 Enzyme System
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