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 μM 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.