Discovery of Keap1-Nrf2 small-molecule inhibitors from phytochemicals based on molecular docking

Various phytochemicals have been reported to protect against oxidative stress. However, the mechanism underlying has not been systematically evaluated, which limited their application in disease treatment. Nuclear factor erythroid 2-related factor 2 (Nrf2), a central transcription factor in oxidative stress response related to numerous diseases, is activated after dissociating from the cytoskeleton-anchored Kelch-like ECH-associated protein 1 (Keap1). The Keap1-Nrf2 protein-protein interaction has become an important drug target. This study was designed to clarify whether antioxidantive phytochemicals inhibit the Keap1-Nrf2 protein-protein interaction and activate the Nrf2-ARE signaling pathway efficiently. Molecular docking and 3D-QSAR were applied to evaluate the interaction effects between 178 antioxidant phytochemicals and the Nrf2 binding site in Keap1. The Nrf2 activation effect was tested on a H₂O₂-induced oxidative-injured cell model. Results showed that the 178 phytochemicals could be divided into high-, medium-, and low-total-score groups depending on their binding affinity with Keap1, and the high-total-score group consisted of 24 compounds with abundant oxygen or glycosides. Meanwhile, these compounds could bind with key amino acids in the structure of the Keap1-Nrf2 interface. Compounds from high-total-score group show effective activation effects on Nrf2. In conclusion, phytochemicals showed high binding affinity with Keap1 are promising new Nrf2 activators.