Molecular Docking, Pharmacophore Mapping And Virtual Screening Of Potent Human P-Glycoprotein Inhibitors

Multidrug resistance (MDR) is a prevalent issue when treating cancer with chemotherapy. For development of inhibitors to combat multidrug resistance in cancer cells, P-glycoprotein (P-gp) serves as therapeutic target. In the quest of new potent human p-glycoprotein modulators, series of compounds were screened through process of molecular docking followed by pharmacophore mapping and virtual screening as a computational tool. For this kind of work natural (piperine, curcumin, quercetin) as well as synthetic (Verapamil) bioenhancers were docked against human P-gp (PDB code: 6C0V) and binding energies were determined. The docking study was performed by using AutoDock vina software and Discovery Studio 2021 Client software. All these bioenhancers showed good docking score with the target protein. Docking was followed by ligand-based pharmacophore detection using PharmaGist webserver. In additament structure-based virtual screening was also performed using Pharmit webserver with goal of identifying lead molecules that bind to target P-gp. Furthermore, virtually screened structures were subjected to Swiss ADME servers for determination of drug-likeness prediction. Based on computational analysis, total of 10 new potent p-gp inhibitor molecules were selected and tested further for their inhibitory potential against human P-gp by molecular docking. Virtually screened molecules exhibit better binding interactions with human P-gp (docking score -10.3) compared to already reported P-gp inhibitors (docking score -8.0). Overall, study proposed, 10 molecules have strong binding efficiency against human P-gp in comparison to most commonly used bioenhancers, thus may be used as putative bioenhancer in therapy. The present study needs further experimental validation to be used as bioenhancers.