In silico approach to find potential inhibitors of p-glycoprotein from piperazine derivatives

Kapare, Abhijig
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University of Delaware
The development of new inhibitor possessing high efficacy, low toxicity and more potency is a pivotal approach to overcome p-glycoprotein (p-gp) mediated multidrug resistance (MDR) in cancer treatment. In this study, we performed drug-designing analysis to find the lead molecules that could inhibit p-glycoprotein (p-gp) by blocking its ATPase activity to counter MDR in cancerous cells. We selected PB28 as the primary ligand, which is a dual inhibitor of p-glycoprotein and MRP1, another protein involved in MDR. Pharmacophore analysis gave idea about the moiety required to bind p-gp. Docking analysis suggested that few molecules have better docking scores than PB28. By Quantitative Structural Analysis Relationship (QSAR) analysis using multiple variable selection by simulated annealing method, we found the most dominant descriptors in analyzing the biological activity (EC50). We validated the 2D and 3D QSAR models on the 12 set of compounds and found that the activity predicted by the two models is almost similar. The study showed that there is a possibility to find the better potent inhibitors than PB28. New piperazine derivatives could be tested in silico by the QSAR model generated by this study for analyzing the biological activity. The lead molecules could be tested on MRP1 and then subjected for clinical trials.