An Energetically Favorable Ligand Entrance Gate of a Multidrug Transporter Revealed by Partial Nudged Elastic Band Simulations.

ABSTRACT: P-glycoprotein (P-gp) is a multidrug transporter, which harnesses the chemical energy of ATP to power the efflux of diverse chemotherapeutics out of cells and thus contributes to the development of multidrug resistance (MDR) in cancer. It has been proved that the ligand-binding pocket of P-gp is located at the transmembrane domains (TMDs). However, the access of ligands into the binding pocket remains to be elucidated, which definitely hinder the development of P-gp inhibitors. Herein, the access pathways of a well-known substrate rhodamine-123 and a cyclopeptide inhibitor QZ-Leu were characterized by time-independent partial nudged elastic band (PNEB) simulations. The decreasing free energies along the PNEB-optimized access pathway indicated that TM4/6 cleft may be an energetically favora

SUBMITTER: Xing J 

PROVIDER: S-EPMC6406077 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature