title: Warfarin resistance associated with genetic polymorphism of VKORC1: linking clinical response to molecular mechanism using computational modeling.
abstract: The variable response to warfarin treatment often has a genetic basis. A protein homology model of human vitamin K epoxide reductase, subunit 1 (VKORC1), was generated to elucidate the mechanism of warfarin resistance observed in a patient with the Val66Met mutation. The VKORC1 homology model comprises four transmembrane (TM) helical domains and a half helical lid domain. Cys132 and Cys135, located in the N-terminal end of TM-4, are linked through a disulfide bond. Two distinct binding sites for warfarin were identified. Site-1, which binds vitamin K epoxide (KO) in a catalytically favorable orientation, shows higher affinity for S-warfarin compared with R-warfarin. Site-2, positioned in the domain occupied by the hydrophobic tail of KO, binds both warfarin enantiomers with similar affinity. Displacement of Arg37 occurs in the Val66Met mutant, blocking access of warfarin (but not KO) to Site-1, consistent with clinical observation of warfarin resistance.
authors.affiliation: aDepartment of Clinical Pharmacology bFlinders Centre for Innovation in Cancer, Flinders University School of Medicine cDepartment of Respiratory Medicine, Flinders Medical Centre dDiscipline of Pharmacology, University of Adelaide School of Medical Sciences, Adelaide, South Australia, Australia.
authors.forename: Benjamin C
authors.initials: BC
authors.lastname: Lewis
authors.forename: Pramod C
authors.initials: PC
authors.lastname: Nair
authors.forename: Subash S
authors.initials: SS
authors.lastname: Heran
authors.forename: Andrew A
authors.initials: AA
authors.lastname: Somogyi
authors.forename: Jeffrey J
authors.initials: JJ
authors.lastname: Bowden
authors.forename: Matthew P
authors.initials: MP
authors.lastname: Doogue
authors.forename: John O
authors.initials: JO
authors.lastname: Miners
mesh_terms: D000328:Adult; D001665:Binding Sites; D004351:Drug Resistance; D006801:Humans; D008297:Male; D008958:Models, Molecular; D009154:Mutation; D020641:Polymorphism, Single Nucleotide; D017433:Protein Structure, Secondary; D011655:Pulmonary Embolism / Q000188:drug therapy* / Q000235:genetics*; D040681:Structural Homology, Protein; D013636:Tanzania; D064417:Vitamin K Epoxide Reductases / Q000737:chemistry / Q000235:genetics*; D014859:Warfarin / Q000008:administration & dosage*
chemical_list: D014859:Warfarin; C578523:VKORC1 protein, human; D064417:Vitamin K Epoxide Reductases