Unlocking Anti-Inflammatory Potential: Virtual Discovery and ADMET Evaluation of Novel Pyrazole-Based COX-II Inhibitors

Abstract

Background Inflammation, a complex biological process mediated by arachidonic acid metabolites, plays a crucial role in various diseases like arthritis, psoriasis and neurodegenerative disorders. The Cyclooxygenase (COX) pathway, particularly COX-2, is a well-established anti-inflammatory target. Materials and Methods This study aimed to discover and evaluate novel pyrazole derivatives as potential COX-2 inhibitors via virtual screening. The 3D crystal structure of Cyclooxygenase-II (PDB: 1CX2) was prepared and optimized for in-silico investigations. Molecular docking analysis using AutoDock Vina assessed ligand-protein interactions, guided by CASTp3.0-predicted binding sites. Ligands were energy minimized and docked against the protein and drug-likeness/synthetic accessibility was predicted using SwissADME and pkCSM. Biological activity and medicinal chemistry were assessed using network diagrams, Bioavailability Radar and BOILED-Egg model for absorption and brain penetration prediction. This integrated approach facilitates the identification of potential COX-2 inhibitors with favorable pharmacokinetic profiles for further development. Results Through molecular docking, three compounds (D202, D305 and F505) exhibited the highest binding affinity for COX-2, surpassing the native ligand’s residual binding. Subsequent ADMET prediction revealed promising pharmacokinetic properties, including significant oral bioavailability scores (0.55) and synthetic feasibility scores ranging from 3.05 to 3.74. Conclusion These findings suggest the potential of these pyrazole derivatives as promising lead candidates for further development as novel anti-inflammatory agents.

Keywords: Inflammation; COX 2; Molecular docking; ADMET; Pyrazole