Do Drugs Have Access to the P-Glycoprotein Drug-Binding Pocket through Gates?

• DOI: 10.1021/acs.jctc.5b00652
• Publication Date: 2015-08-31T18:35:29Z
• Authors: Ricardo J. Ferreira; Maria-José U. Fer...; Daniel J. V. A. d...
• Keywords: 0301 basic medicine; 03 medical and health sciences; Binding Sites; Molecular Structure; Quinolines; Humans; Thermodynamics; ATP Binding Cassette Transporter, Subfamily B, Member 1; Molecular Dynamics Simulation; Colchicine

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.