Do Drugs Have Access to the P-Glycoprotein Drug-Binding Pocket through Gates?
The P-glycoprotein efflux mechanism is being studied since its identification as a leading protagonist in multidrug resistance. Recently, it was suggested that drugs enter the drug-binding pocket (DBP) through gates located between the transmembrane domains. For both a substrate and a modulator, the potential of mean force curves along the reaction coordinate obtained with the WHAM approach were similar, with no activation energy required for crossing the gate. Moreover, drug transit from bulk water into the DBP was characterized as an overall free-energy downhill process.
Ricardo J. Ferreira†, Maria-José U. Ferreira†, and Daniel J. V. A. dos Santos*‡
† Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Avenida Prof. Gama Pinto, 1649-003 Lisboa, Portugal‡ REQUIMTE, Department of Chemistry & Biochemistry, Faculty of Sciences, University of Porto, Rua do Campo Alegre, 4169-007 Porto, Portugal
http://dx.doi.org/10.1021/acs.jctc.5b00652