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...

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Veröffentlicht in:	Journal of chemical theory and computation 2015-10, Vol.11 (10), p.4525-4529
Hauptverfasser:	Ferreira, Ricardo J, Ferreira, Maria-José U, dos Santos, Daniel J. V. A
Format:	Artikel
Sprache:	eng
Schlagworte:	ATP-Binding Cassette, Sub-Family B, Member 1 - antagonists & inhibitors ATP-Binding Cassette, Sub-Family B, Member 1 - chemistry Binding Sites - drug effects Colchicine - chemistry Colchicine - pharmacology Computation Drugs Efflux Gates Humans Mathematical models Modulators Molecular Dynamics Simulation Molecular Structure Pocket Quinolines - chemistry Quinolines - pharmacology Thermodynamics Transit
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creator	Ferreira, Ricardo J Ferreira, Maria-José U dos Santos, Daniel J. V. A
description	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.
doi_str_mv	10.1021/acs.jctc.5b00652
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subjects	ATP-Binding Cassette, Sub-Family B, Member 1 - antagonists & inhibitors ATP-Binding Cassette, Sub-Family B, Member 1 - chemistry Binding Sites - drug effects Colchicine - chemistry Colchicine - pharmacology Computation Drugs Efflux Gates Humans Mathematical models Modulators Molecular Dynamics Simulation Molecular Structure Pocket Quinolines - chemistry Quinolines - pharmacology Thermodynamics Transit
title	Do Drugs Have Access to the P‑Glycoprotein Drug-Binding Pocket through Gates?
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