Integrative computational approach for hyperuricemia treatment: 3D QSAR, molecular docking and dynamics of flavonoid analogues as xanthine oxidase inhibitors

Hyperuricemia is characterized by an excessive accumulation of uric acid in the joints, and this condition remains a therapeutic challenge with limited options and significant side effects associated with conventional pharmacological treatments. This research aims to identify new molecular structures capable of inhibiting uric acid production by targeting key enzymes in purine metabolism. In this study, a comprehensive in silico analysis was conducted to explore the relationship between the chemical structure of flavonoid analogs and their inhibitory capacity on xanthine oxidase (XO). The results revealed that the analogs meet the structural requirements for xanthine oxidase inhibition. A 3D-QSAR model was generated, accurately predicting the biological activity of flavonoids targeting XO and identifying a potential lead compound with a q2 of 0.77 and R2 of 0.98. The CoMFA analysis disclosed how substituents affect XO affinity, with bulky groups enhancing it at positions R2 and R7. These strategies were applied and a new molecule was generated with better binding energy with the XO receptor. Electron-donating or accepting groups, such as phenyl and carbonyl, interact with amino acid residues (T1010 and R880) in XO's active site. Molecular docking analysis highlights different common interaction types in flavonoid-XO binding, emphasizing the importance of hydrogen and C-H - H bonds. Previous studies underscore the significance of these specific residues in flavonoid-XO binding. Molecular dynamics showed that 3(R,S)-3 '-Hydroxy-8-methoxyvestitol R,S )-3 '-Hydroxy-8-methoxyvestitol predominantly interacts through hydrophobic interactions, inducing a conformational change in the binding pocket and stabilizing the complex along with stable hydrogen bonds.