SHORT COMMUNICATIONWarfarin resistance associated with genetic polymorphism of VKORC1 linking clinical response to molecular mechanism using computational modelingLewis, Benjamin C.a,b,*; Nair, Pramod C.a,b,*; Heran, Subash S.c; Somogyi, Andrew A.d; Bowden, Jeffrey J.c; Doogue, Matthew P.a; Miners, John O.a,bAuthor Information 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 * Benjamin C. Lewis and Pramod C. Nair contributed equally to the writing of this article. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's website (www.pharmacogeneticsandgenomics.com). Present address: Matthew P. Doogue: Department of Clinical Pharmacology, Christchurch Hospital, Christchurch 4710, New Zealand Correspondence to Benjamin C. Lewis, BSc, PhD, MRACI CCHEM, Department of Clinical Pharmacology, Flinders University School of Medicine, Flinders Medical Centre, Bedford Park, South Australia 5042, Australia Tel: +61 8 82044031; fax: +61 8 82045114; e-mail: [email protected] Received July 20, 2015 Accepted September 28, 2015 Pharmacogenetics and Genomics: January 2016 - Volume 26 - Issue 1 - p 44-50 doi: 10.1097/FPC.0000000000000184 Buy SDC Metrics 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. Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.