Identification of novel inhibitors of Keap1/Nrf2 by a promising method combining protein-protein interaction-oriented library and machine learning.

ABSTRACT: Protein-protein interactions (PPIs) are prospective but challenging targets for drug discovery, because screening using traditional small-molecule libraries often fails to identify hits. Recently, we developed a PPI-oriented library comprising 12,593 small-to-medium-sized newly synthesized molecules. This study validates a promising combined method using PPI-oriented library and ligand-based virtual screening (LBVS) to discover novel PPI inhibitory compounds for Kelch-like ECH-associated protein 1 (Keap1) and nuclear factor erythroid 2-related factor 2 (Nrf2). We performed LBVS with two random forest models against our PPI library and the following time-resolved fluorescence resonance energy transfer (TR-FRET) assays of 620 compounds identified 15 specific hit compounds. The high hit rates

SUBMITTER: Shimizu Y 

PROVIDER: S-EPMC8016952 | biostudies-literature | 2021 Apr

REPOSITORIES: biostudies-literature