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Molecular Docking characterizes substrate-binding sites and efflux modulation mechanisms within P-glycoprotein.


J Chem Inf Model. 2013 Jun 26;


Authors: Ferreira RJ, Ferreira MJ, Dos Santos DJ


Abstract

P-Glycoprotein (Pgp) is one of the best characterized ABC transporters, often involved in the multidrug-resistance phenotype expressed 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 all 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 herein defined for the first time between both Pgp halves, 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.

PMID: 23802684 [PubMed - as supplied by publisher]