Distal effect of amino acid substitutions in CYP2C9 polymorphic variants causes differences in interatomic interactions against (S)-warfarin

PLoS One. 2013 Sep 2;8(9):e74053. doi: 10.1371/journal.pone.0074053. eCollection 2013.


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.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Substitution*
  • Cytochrome P-450 Enzyme System / chemistry
  • Cytochrome P-450 Enzyme System / genetics*
  • Cytochrome P-450 Enzyme System / metabolism*
  • Molecular Docking Simulation
  • Molecular Dynamics Simulation
  • Polymorphism, Genetic*
  • Protein Binding
  • Protein Conformation
  • Substrate Specificity
  • Warfarin / metabolism*


  • Warfarin
  • Cytochrome P-450 Enzyme System