文章基本信息

标题：Identification of novel inhibitors of Keap1/Nrf2 by a promising method combining protein–protein interaction-oriented library and machine learning
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作者：Yugo Shimizu ; Tomoki Yonezawa ; Junichi Sakamoto 等
期刊名称：Scientific Reports
电子版ISSN：2045-2322
出版年度：2021
卷号：11
DOI：10.1038/s41598-021-86616-1
语种：English
出版社：Springer Nature
摘要：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 for the entire PPI library (estimated 0.56–1.3%) and the LBVS (maximum 5.4%) compared to a conventional screening library showed the utility of the library and the efficiency of LBVS. All the hit compounds possessed novel structures with Tanimoto similarity ≤ 0.26 to known Keap1/Nrf2 inhibitors and aqueous solubility (AlogP < 5). Reasonable binding modes were predicted using 3D alignment of five hit compounds and a Keap1/Nrf2 peptide crystal structure. Our results represent a new, efficient method combining the PPI library and LBVS to identify novel PPI inhibitory ligands with expanded chemical space.