Excited-state genistein and its methoxy derivatives with improved antioxidant activity: DFT/TD-DFT calculations, molecular docking, and molecular dynamic simulation.

Oxidative stress from excessive accumulation of ROS drives several diseases, highlighting the need for efficient antioxidants. The antioxidant activity of excited-state genistein (Gen) and its methylated derivatives (5-MG, 4'-MG, and 7-MG) is systematically explored using density functional theory/time-dependent density functional theory (DFT/TD-DFT) calculations, molecular docking, and molecular dynamics simulation. Except for 5-MG, the rest of the isoflavones have excited state intramolecular proton transfer (ESIPT) property confirmed by potential energy curves as an ultrafast process, which further determines the molecular forms, namely enol (S) and keto* (S) forms. Especially important, the excited-state isoflavones significantly exhibit increased highest occupied molecular orbital (HOMO) energy value, namely, the enhanced antioxidant activity, with the ESIPT property playing a critical role. Moreover, the introduction of methoxy at 4' and 7 sites enhances the antioxidant activity, while the phenolic hydroxyl group remains the critical moiety for the antioxidant activity to function as confirmed by atomic dipole moment corrected Hirshfeld population (ADCH). Molecular docking analysis indicates that the binding energy of the excited-state isoflavone to xanthine oxidase (XO) is extremely low, proving that it has a strong inhibitory effect on XO. Furthermore, molecular dynamics simulation demonstrates the stability of the docking model.