Novel protein-protein interaction inhibitor of Nrf2-Keap1 discovered by structure-based virtual screening

Herein we first reported hierarchical structure-based virtual screening utilizing the receptor-ligand binding model of Nrf2-Keap1. The most promising compound, 15, which is one of the most potent direct PPI inhibitors of Nrf2-Keap1 reported so far, can effectively disrupt the Nrf2-Keap1 interaction with the in vitro EC50 of 9.80 mu M in the fluorescence polarization (FP) assay. 15 can also activate the Nrf2 transcription activity in the cell-based ARE-luciferase reporter assays in a dose-dependent manner. The compound can serve as a promising starting point for the discovery of potent inhibitors of Nrf2-Keap1 interaction.