Enhancing Antioxidant and Anti-Inflammatory Activities of ESIntraPT/ESInterPT-Type 6-Methoxyflavone: Insights from DFT/TD-DFT, Molecular Docking, and Molecular Dynamics Simulations

Development of antioxidant-type anti-inflammatory inhibitors is essential to mitigate free radical-mediated inflammatory damage, where natural flavonoids with multiple bioactivities are promising candidate compounds. By employing density functional theory/time-dependent density functional theory, molecular docking, and molecular dynamics simulations, the association between excited-state intramolecular/intermolecular proton transfer (ESIntraPT/ESInterPT) mechanisms and antioxidant/anti-inflammatory activity of 6-methoxyflavonol (6-MF) is elucidated. To simulate the ESIntraPT/ESInterPT process, three conditions are set: gas phase, water phase (implicit solvent), and an explicit water molecule. Based on Hirshfeld surface and potential energy curves, the results suggest that excited-state 6-MF in the water phase tends to occur in the ESInterPT process rather than the ESIntraPT process. Density-of-state combined with frontier molecular orbitals demonstrates that antioxidant activity is enhanced during the ESIntraPT process. Molecular docking reveals that keto-form 6-MF has lower binding energy to cyclooxygenase-2 (COX-2) and forms interactions with critical amino acid residues such as TYR385, indicating its anti-inflammatory activity. 50-ns molecular dynamics simulation further confirms the stability of the enol-/keto-6-MF-COX-2 complex.