In silico exploration of phenytoin binding site in two catalytic states of human P-glycoprotein models

Indian J Biochem Biophys. 2013 Feb;50(1):7-13.


P-glycoprotein (P-gp), an ATP-dependant efflux pump transports a wide range of substrates across cellular membranes. Earlier studies have identified drug efflux due to the over-expression of P-gp as one of the causes for the resistance of phenytoin, an anti-epileptic drug (AED). While no clear evidence exists on the specific characteristics of phenytoin association with the human P-gp, this study employed structure-based computational approaches to identify its binding site and the underlying interactions. The identified site was validated with that of rhodamine, a widely accepted reference and an experimental probe. Further, an in silico proof-of-concept for phenytoin interactions and its decreased binding affinity with the closed-state of human P-gp model was provided in comparison with other AEDs. This is the first report to provide insights into the phenytoin binding site and possibly better explain its efflux by P-gp.

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / chemistry*
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / ultrastructure*
  • Binding Sites
  • Catalysis
  • Computer Simulation
  • Humans
  • Models, Chemical*
  • Models, Molecular*
  • Phenytoin / chemistry*
  • Protein Binding
  • Protein Conformation


  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Phenytoin