Exploring Potential COX‐2 Inhibitors of Ibuprofen Derivatives: Integrating DFT, Molecular Docking, Molecular Dynamics Simulations, ADMET with FEL and MMPBSA Analyses

Abstract Ibuprofen, a widely used NSAID, suppresses COX‐2‐mediated prostaglandin synthesis to alleviate inflammation, pain, and fever; however, it is associated with significant adverse effects attributable to its carboxylic acid group (─COOH). In this study, 14 ibuprofen derivatives were designed through the modification of their ─COOH group with acyl and amide derivatives of substituted phenyl and heterocyclic moieties to increase their therapeutic efficacy while mitigating adverse effects. The molecular structures were subjected to optimization via density functional theory (DFT), and the thermodynamic stability, spectroscopic characteristics, and electronic properties were determined. Chemical reactivity descriptors were also assessed to evaluate their prospective biological activity. Molecular docking analyses against COX‐2 demonstrated that the majority of the derivatives exhibited greater binding affinities than did ibuprofen (−7.3 kcal/mol), particularly I7 (−9.0 kcal/mol) and I9 (−8.8 kcal/mol). Molecular dynamics simulations conducted throughout 100 ns further validated the conformational stability and binding configurations of the I7 ‐5KIR complex. MMPBSA energy analysis revealed that the I7 ‐5KIR complex possessed a free binding energy of −78.020 kJ/mol, whereas free energy landscape (FEL) analysis predicted its conformational stability, with energy values reaching 17.9 kJ/mol. Additionally, in silico ADMET analysis suggested favorable drug‐like characteristics coupled with diminished toxicity, indicating their potential as COX‐2 inhibitors and anti‐inflammatory agents.