Molecular recognition between potential natural inhibitors of the Keap1-Nrf2 complex

Disrupting the Keap1-Nrf2 pathway enhances Nrf2 activity, which has been identified as an important approach for the prevention of different chronic diseases in which oxidative stress and inflammation are present, such as cancer, diabetes, Alzheimer's and Parkinson's. Based on the high potential to modulate antioxidant, anti-inflammatory and anticancer properties that the discovery of Keap1-Nrf2 protein–protein interaction inhibitors would represent, the utilization of some natural compounds has emerged as a promising strategy to identify new drugs. To gain insight into the structural and energetic basis of the molecular recognition between some natural inhibitors that could work as inhibitors of the Keap1-Nrf2 complex, we evaluated the binding properties between four natural compounds present in the extract of Geranium schiedeanum (Gs): 3-O-a-L arabinofuranoside-7-O-a-L-rhamnopyranoside of kaempferol (KAM), gallic acid (GAL), ellagic acid (ELL) and geranium acetonitrile (ACE), which based on experimental findings have been proposed as possible Keap1-Nrf2 PPI inhibitors. Computational studies combining docking and MD simulations accompanied by the MMGBSA approach revealed that KAM and ACE directly interact with residues in the Kelch domain that participate in the molecular recognition of Nrf2, indicating that both natural compounds could act as activators of Nrf2, whereas GAL and ELL are possible free radical scavengers.