Exploring the binding mechanism of 4-difluoromethyl pyrazole derivatives to cyclooxygenase-2: insights from DFT and molecular docking

This study aimed to evaluate a series of novel 4-difluoromethyl pyrazole derivatives (3a-3h) as potential COX-2 inhibitors using an integrated computational approach. Molecular docking simulations were performed against the murine COX-2 structure (PDB ID: 3LN1) to predict binding modes and calculate binding affinities. Density Functional Theory (DFT) calculations were employed to determine Frontier Molecular Orbital (FMO) energies and Molecular Electrostatic Potential (MEP) surfaces to complement the docking results. Docking studies revealed that compounds 3a and 3f exhibited the highest binding affinities, with docking scores indicating strong interactions within the COX-2 active site under the static protein environment. The superior affinity of these compounds was attributed to the formation of three hydrogen bonds and multiple hydrophobic interactions with key amino acid residues. Compound 3g also demonstrated a favourable binding energy score of −6.98 kcal/mol, suggesting stable complex formation. However, during the MD simulations compounds 3a and 3f were performing moderately while 3b, 3d, and 3g demonstrated enhanced stability under the dynamic conditions based on the multiple stability metrics. The integrated computational approach successfully identified compounds 3b, 3d and 3g as the most promising COX-2 inhibitors within this series for the rational design of more potent anti-inflammatory agents.