Molecular Docking Characterizes Substrate-Binding Sites and Efflux Modulation Mechanisms within P-Glycoprotein.

Abstract

P-Glycoprotein (Pgp) is one of the best characterized ABC transporters, often involved in the multidrug-resistance phenotype overexpressed by several cancer cell lines. Experimental studies contributed to important knowledge concerning substrate polyspecificity, efflux mechanism, and drug-binding sites. This information is, however, scattered through different perspectives, not existing a unifying model for the knowledge available for this transporter. Using a previously refined structure of murine Pgp, three putative drug-binding sites were hereby characterized by means of molecular docking. The modulator site (M-site) is characterized by cross interactions between both Pgp halves herein defined for the first time, having an important role in impairing conformational changes leading to substrate efflux. Two other binding sites, located next to the inner leaflet of the lipid bilayer, were identified as the substrate-binding H and R sites by matching docking and experimental results. A new classification model with the ability to discriminate substrates from modulators is also proposed, integrating a vast number of theoretical and experimental data.

In silico Study on the Interaction between P-glycoprotein and Its Inhibitors at the Drug Binding Pocket

“…The recent docking study, however, proposed that the verapamil binding site was different from "R" site, not only from "H" site. 32 The result of this docking study is controversial comparing to our result of docking study that verapamil binding site is similar to "R" site. Verapamil was known as the ligand which preferentially binds to "H" site in 1990's.…”

QSAR and docking studies of some 1,2,3,4-tetrahydropyrimidines: evaluation of gp41 as possible target for anti-HIV-1 activity

“…Structure-based approaches which are also called protein-based studies are the most useful methods when the structure of the receptor, usually a protein, is available. They deal with modeling the ligand-receptor interactions through docking (Vitale et al, 2013;Ferreira et al, 2013;Shahlaei et al, 2013) and a more accurate method, molecular dynamics (MD) simulation (Hucke et al, 2014;Chavan et al, 2011;Shahlaei et al, 2011). Such studies provide information on possible types of interaction forces between the ligand and its receptor and also information on the nature of the receptor.…”

Enzastaurin inhibits ABCB1-mediated drug efflux independently of effects on protein kinase C signalling and the cellular p53 status

“…Recent analyses had shown that docking studies performed by various approaches are reliable strategies to identify compounds that interact directly with ABCB1 [51][52][53]. From our previous studies, the docking scores obtained for a group of 54 substrates (including well-known substrates such as ivermectin and cyclosporine) had an average docking score of ≤ −12, like those we observed for enzastaurin in the 3G60 structure, while a group of 69 nonsubstrates had an average score of ~ −10 kcal/mol using MOE software and the same docking methodology [54,55].…”