Molecular Docking and dynamic simulation analysis of flavonoid derivatives as COX-2 inhibitors.

ABSTRACT

Cyclooxygenase-2 (COX-2) is a key enzyme involved in inflammation and tumor progression, playing a significant role in the development of various cancers, including colorectal, breast, lung, and prostate cancers. In this study, molecular docking and molecular dynamics (MD) simulations were conducted to evaluate the binding potential and stability of flavonoid compounds as potential COX-2 inhibitors. A total of 36 flavonoid compounds were selected based on pharmacokinetic properties and subjected to molecular docking analysis. Binding affinity calculations revealed that several flavonoids exhibited strong interactions with COX-2, with Cudraflavone A showing the highest binding affinity of - 10.19 kcal/mol, surpassing the standard inhibitor Rofecoxib (- 9.4 kcal/mol). Key interactions were identified with critical active site residues, including Tyr130, Glu465, and Arg44, through hydrogen bonding and hydrophobic interactions. To further assess the stability of the COX-2-flavonoid complex, molecular dynamics simulations were performed using GROMACS. Root-mean-square deviation (RMSD) analysis demonstrated that the COX-2-Cudraflavone A complex exhibited greater structural stability compared to the unbound enzyme. Root-mean-square fluctuation (RMSF) analysis indicated reduced flexibility in key regions of the enzyme upon ligand binding, reinforcing its stabilizing effect. Additionally, the radius of gyration (Rg) analysis confirmed that the complex maintained a more compact conformation, suggesting enhanced structural integrity. These findings suggest that Cudraflavone A is a promising candidate for COX-2 inhibition, exhibiting superior binding affinity and stabilizing effects. This study provides valuable insights into the potential development of flavonoid-based COX-2 inhibitors for cancer and anti-inflammatory therapeutics.

SUPPLEMENTARY INFORMATION

The online version contains supplementary material available at 10.1007/s40203-025-00349-x.