Structural tuning of diclofenac for enhanced medicinal efficacy and reduced adverse effects: an integrating computational validation

), and it was confirmed by the number of H-bonds, π-π stacking, and hydrophobic interactions with the key residues. The results of 100 ns molecular dynamics simulations revealed that DCF, DCF2, DCF4, and DCF6 can form tight-binding complexes with 5IKR, which carries the optimal binding affinity and structural stability. ADMET projections indicated elevated intestinal absorption, permeability across the blood-brain barrier, effective renal excretion, favorable biodegradability, and reduced acute oral toxicity for many analogues, particularly DCF4-DCF6. PASS prediction validated the retention of fundamental antipyretic, anti-inflammatory, and analgesic properties, while indicating a tendency for reduced ulcerogenic and hepatotoxic risks in certain derivatives. This study highlights DCF2, DCF4, and DCF6 as promising DCF-based candidates for further optimization and experimental validation as part of safe and more effective NSAIDs.