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Title: In silico exploration of phenytoin binding site in two catalytic states of human P-glycoprotein models
Authors: Cleave A, Suneetha Susan
Panda, Roshni
Suresh, P K
Keywords: P-Glycoprotein;Multidrug resistance;Phenytoin;Efflux;Drug binding site;In silico
Issue Date: Feb-2013
Publisher: NISCAIR-CSIR, India
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.
Page(s): 7-13
ISSN: 0975-0959 (Online); 0301-1208 (Print)
Appears in Collections:IJBB Vol.50(1) [February 2013]

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