Identification and Empiric Evaluation of New Inhibitors of the Multidrug Transporter P-Glycoprotein (ABCB1).

ABSTRACT: The expression of the drug efflux pump ABCB1 correlates negatively with cancer survival, making the transporter an attractive target for therapeutic inhibition. In order to identify new inhibitors of ABCB1, we have exploited the cryo-EM structure of the protein to develop a pharmacophore model derived from the best docked conformations of a structurally diverse range of known inhibitors. The pharmacophore model was used to screen the Chembridge compound library. We identified six new potential inhibitors with distinct chemistry compared to the third-generation inhibitor tariquidar and with favourable lipophilic efficiency (LipE) and lipophilicity (CLogP) characteristics, suggesting oral bioavailability. These were evaluated experimentally for efficacy and potency using a fluorescent drug t

SUBMITTER: Cheema Y 

PROVIDER: S-EPMC10049699 | biostudies-literature | 2023 Mar

REPOSITORIES: biostudies-literature