Computational Design and Evaluation of Modified AEW-1 Chalcone Derivatives as Potential Anti-Inflammatory Agents

Abstract

Long-term therapy of inflammation is limited by gastrointestinal, cardiovascular, and renal side effects, motivating the search for safer, multi-target anti-inflammatory agents. The chalcone derivative AEW-1, which exhibits in vivo anti-inflammatory activity comparable to ibuprofen, was selected for rational optimization. Three new AEW-1 derivatives were designed by introducing trihydroxy substitutions on the A ring and evaluated in silico using target prediction, molecular docking, and pharmacokinetic/drug-likeness prediction. Target prediction indicated iNOS as the most probable target for AEW-1 and all its derivatives, supporting iNOS as an additional anti-inflammatory target alongside COX-2. For docking to COX-2, compound 1 exhibited the best binding profile and showed a binding affinity comparable to that of the native ligand, with key interactions involving Ser530. For docking to iNOS, compound 1 also demonstrated the most favorable profile among the derivatives and formed a hydrogen bond with Glu377, a key residue. However, its binding affinity was lower than that of the native ligand. All AEW-1 derivatives satisfied drug-likeness criteria and exhibited improved pharmacokinetic profiles compared to AEW-1. Overall, compound 1, consistent with the 2,4,6-trihydroxy substitution pattern, emerged as the most promising candidate as a dual COX-2/iNOS inhibitor, warranting further validation through molecular dynamics simulations and in vitro enzyme inhibition assays.