Discovery of Azole‐Based COX‐2 Inhibitors Targeting Neuroinflammation in Alzheimer's Disease Via Integrated QSAR‐Based Virtual Screening, Molecular Docking, and Molecular Dynamics

Neuroinflammation is a major contributor to the pathophysiology of Alzheimer's disease (ADs), a progressive neurodegenerative disorder characterized by cognitive decline. Cyclooxygenase‐2 (COX‐2) has been strongly implicated in neuroinflammatory pathways, making it a promising therapeutic target. This study employed a CADD framework to identify azole‐based COX‐2 inhibitors with potential anti‐AD's activity. Robust QSAR models were developed using 99 azole derivatives ( R 2 = 0.707–0.799, Q 2 LOO = 0.559–0.644) and applied to virtually screen 11,000 azole compounds from the ChEMBL database. From these, 827 candidates with predicted IC 50 < 5 µM were selected for molecular docking against COX‐2 (PDB ID 5IKQ). Compound 725 emerged as the top candidate, displaying the most favorable binding with a CDOCKER interaction energy of −53.63 kcal/mol and predicted IC 50 of 1.46 µM, outperforming the reference inhibitor meclofenamic acid. Further, MD simulations (300 ns), free energy landscape analysis, principal component analysis, and MM/GBSA calculations confirmed the stability and favorable energetics of the 725‐5IKQ complex. In silico ADMET profiling further demonstrated its drug‐likeness and safety. Although limited by reliance on computational predictions and a single receptor structure, this study provides a strong foundation. Future experimental validation and scaffold optimization of compound 725 may advance its therapeutic potential for ADs.