Structural modification of mefenamic acid to enhance medicinal efficacy and reduce toxicological effect: a DFT and...

Mefenamic acid (MFC) is a potent NSAID prescribed for the treatment of various inflammatory disorders but infamous for its undesirable effects, including gastrointestinal dysfunctions, renal damage, and risk of cardiovascular complications. Studies in this direction were planned to undertake the computational description of sixteen MFC analogues to optimize their pharmacological properties and minimize toxicity. In the current study, we aimed to discuss MFC and its analogues as safe, promising, effective, novel anti-inflammatory, anti-nociceptive agents through thermodynamic analysis utilizing molecular docking study, MD simulation, ADMET, and PASS prediction. Thermodynamic studies revealed that MFC3 and MFC7 were more stable than their analogues, with lower free energies and higher dipole moments, suggesting strong intermolecular interactions. Furthermore, the results of molecular docking indicated that MFC derivatives, particularly MFC1, MFC7, MFC12, and MFC16, had higher COX-2 binding affinity than MFC, suggesting that those compounds may have stronger therapeutic activity against inflammation. It was additionally proved that the stable protein-ligand binding interactions targeted to the derivatives were conserved via molecular dynamic simulations, whereby strong H-bonds and frameshift fluctuations stabilized the complex. According to ADMET and PASS predictions, some derivatives exhibited strong oral bioavailability, low toxicity, and more effective anti-inflammatory and analgesic effects as favorable pharmacokinetic properties. In conclusion, our data suggest that MFC analogues may represent a more efficacious and less toxic treatment. Thus, they may be promising candidates for more clinical trials and experimental validation. These results provide a conceptual framework for the optimization of MFC analogs in the therapy of pain and inflammation.

The online version contains supplementary material available at 10.1007/s40203-026-00647-y.