title: In silico exploration of phenytoin binding site in two catalytic states of human P-glycoprotein models.
abstract: 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.
authors.affiliation: School of Biosciences and Technology, VIT University, Vellore, India.
authors.forename: Suneetha Susan A
authors.initials: SS
authors.lastname: Cleave
authors.forename: Roshni
authors.initials: R
authors.lastname: Panda
authors.forename: P K
authors.initials: PK
authors.lastname: Suresh
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000737:chemistry* / Q000648:ultrastructure*; D001665:Binding Sites; D002384:Catalysis; D003198:Computer Simulation; D006801:Humans; D008956:Models, Chemical; D008958:Models, Molecular; D010672:Phenytoin / Q000737:chemistry*; D011485:Protein Binding; D011487:Protein Conformation
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D010672:Phenytoin