The Search for Cyclooxygenase-2 (COX-2) Inhibitors for the Treatment of Inflammation Disease: An in-silico Study

Cyclooxygenase (COX-2) has been validated as a molecular target for treating inflammatory diseases. The present work was performed to identify potential COX-2 inhibitors by employing pharmacophore modeling.

The pharmacophore features consisted of seven features, ie, three hydrophobic, one negative ion, and three hydrogen bond acceptors, which were developed based on the structure of COX-2 inhibitor, (R)-naproxen.

The pharmacophore model was validated with a Goodness of Hit (GH score) of 0.754 and the values of AUC100% 0.51. Screening against the ZINC database retrieved 1675 hits, while the molecular docking procedure identified four best hit molecules in term of binding orientation and binding energies, ie, Lig_1805/ZINC103584272 (E = -11.03 kcal/mol), Lig_553/ZINC408573132 (E = -10.92 kcal/mol), Lig_680/ZINC103584263 (E = -10.90 kcal/mol), and Lig_2006/ZINC19324645 (E = -10.62 kcal/mol).

The interactions of the four hits occurred in the binding site as (R)-naproxen did, and interestingly, their binding affinities were stronger than (R)-naproxen, implying their potential as COX-2 inhibitors.