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.