Cleave Suneetha Susan A, Panda Roshni, Suresh P K
School of Biosciences and Technology, VIT University, Vellore, India.
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.
P-糖蛋白（P-gp）是一种依赖ATP的外排泵，可跨细胞膜转运多种底物。早期研究已确定，P-gp过度表达导致的药物外排是抗癫痫药物（AED）苯妥英耐药的原因之一。虽然目前尚无明确证据表明苯妥英与人P-gp结合的具体特性，但本研究采用基于结构的计算方法来确定其结合位点及潜在相互作用。所确定的位点与广泛认可的参考物及实验探针罗丹明的位点进行了验证。此外，与其他AED相比，还提供了苯妥英相互作用及其与人P-gp模型关闭状态结合亲和力降低的计算机概念验证。这是第一份深入了解苯妥英结合位点并可能更好地解释其被P-gp外排的报告。
