Mechanistic insights into the effect of

To evaluate the impact of and variants on binding and hydroxylation of warfarin. Multiple linear regression model of warfarin pharmacokinetics was developed from the dataset of patients (n = 199). Pymol based models were developed for the genetic variants. and variants exhibited high warfarin/7-hydroxywarfarin (multiple linear regression model), dose-dependent disruption of hydrogen bonds with warfarin, dose-dependent increase in the distance between C7 of S-warfarin and Fe-O of CYP2C9, dose-dependent decrease in the glide scores ( ). and variants result in disruption of hydrogen bonding interactions with warfarin and longer distance between C7 and Fe-O thus impairing warfarin 7-hydroxylation due to lower binding affinity of warfarin. Original submitted 7 May 2014; Revision submitted 30 October 2014