In Silico Prediction of Binding Affinity of Drugs Against P-Glycoprotein

Abstract

P-glycoprotein (P-gp) is a plasma membrane efflux transporter belonging to ATP-binding superfamily, responsible for multidrug resistance in tumor cells. Over-expression of P-gp in cancer cells limits the efficacy of many anticancer drugs. A clear understanding of P-gp substrate binding will be advantageous in early drug discovery process. However, substrate poly-specificity of P-gp is a limiting factor in rational drug design. In this investigation, we report a dynamic trans-membrane model of P-gp that accurately identified the substrate binding residues of known anticancer agents. The study included homology modeling of human P-gp based on the crystal structure of Murine P-gp, molecular docking, molecular dynamics analyses and binding free energy calculations. The model was further utilized to speculate substrate propensity of in-house anticancer compounds. The model demonstrated promising results with one anticancer compound Noscapine and its derivatives (Amino-noscapine and Bromonoscapine). As per our observations, the molecules could be a potential lead for anticancer agents devoid of P-gp mediated multiple drug resistance.