Optimizing Targeted Inhibitors of P-Glycoprotein Using Computational and Structure-Guided Approaches.

ABSTRACT: Overexpression of ABC transporters like P-glycoprotein (P-gp) has been correlated with resistances in cancer chemotherapy. Intensive efforts to identify P-gp inhibitors for use in combination therapy have not led to clinically approved inhibitors to date. Here, we describe computational approaches combined with structure-based design to improve the characteristics of a P-gp inhibitor previously identified by us. This hit compound represents a novel class of P-gp inhibitors that specifically targets and inhibits P-gp ATP hydrolysis while not being transported by the pump. We describe here a new program for virtual chemical synthesis and computational assessment, ChemGen, to produce hit compound variants with improved binding characteristics. The chemical syntheses of several variants, effic

SUBMITTER: Wise JG 

PROVIDER: S-EPMC7031812 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature