Unveiling the Solvation Behavior and Dynamics of Phenolic Acids and Their Biological Relevance to Modulate Oxidative Stress

Abstract We have carried out classical molecular dynamics simulations to explore the aqueous hydrogen bonding structure of gallic (GAL), syringic (SYR), and ellagic (ELA) acids at 298 K. Further, we have investigated the effects of these phenolic acids on the Keap1–Nrf2 signaling pathway. The center‐of‐mass radial distribution functions show that more water molecules are accumulated around ELA than GAL and SYR. These phenolic acids exhibit a higher tendency to donate their hydrogen atoms than their ability to accept hydrogen from water. Both GAL and SYR form stable H‐bonds with water as compared to ELA. The solvation‐free energy of SYR is −46.54 kJ/mol, while ELA has almost twice the value of GAL (−48.05 kJ/mol). The translational dynamics of ELA are slower compared to GAL and SYR. Our calculated self‐diffusion values of GAL and SYR are close to the experimental observations. All three compounds show favorable characteristics for oral bioavailability and human administration. The computational analysis suggested that ELA has a higher binding affinity to Keap1 than GAL and SYR. A higher number of hydrogen bonding interactions among ELA and Keap1 facilitates the dissociation of Keap1 and Nrf2. The highest binding free energy (−122.05 kJ/mol) of ELA with Keap1 makes it a potent inhibitor of Keap1 and Nrf2 interactions that facilitate the signaling pathway and becomes a potential candidate to modulate oxidative stress.