Molecular-level insights into the antioxidant mechanisms of amide-modified gallic acid derivatives through combined DFT, molecular docking and molecular dynamics simulations

Reactive oxygen species (ROS) contribute to cellular damage, highlighting the importance of effective antioxidants. In this study, four recently reported amide-modified gallic acid derivatives (GAD1-GAD4) have been systematically investigated using Density Functional Theory (DFT), molecular docking, and molecular dynamics (MD) simulations to elucidate their antioxidant activity and interactions with Xanthine Oxidase (XO), an enzyme involved in ROS generation. DFT analysis has revealed that GAD3 has exhibited the lowest HOMO–LUMO gap (7.218 eV), while Hydrogen Atom Transfer (HAT) analysis has identified OH3 as the most favourable radical-scavenging site in GAD1, GAD2, and GAD4, whereas OH2 has been identified as the preferred site in GAD3 based on the lowest BDE values. Molecular docking has further shown that GAD3 has exhibited the most favourable docking score (−10.455 kcal/mol), followed by GAD1 (−10.093 kcal/mol), indicating strong binding affinity towards XO. Furthermore, 100 ns MD simulations confirmed the stability of the GAD-XO complexes through RMSD, RMSF, and Protein–Ligand contact analyses. These findings provide valuable insights into the potential role of GADs in antioxidant therapy, reinforcing their significance in medicinal chemistry.