Design and Molecular Docking Study of Novel 2H-Chromene Derivatives as Potential Cyclooxygenase-2 (COX-2) Inhibitors

Abstract

Cyclooxygenase-2 (COX-2) is a key inducible enzyme of the arachidonic acid cascade and a well-validated target for anti-inflammatory drug design. The 2H-chromene scaffold is a privileged heterocyclic core associated with anti-inflammatory, antioxidant and anticancer activities. In this work, five 2-methyl-2H-chromene derivatives (C1-C5), computationally designed in silico (not yet synthesized or experimentally characterized) and bearing an open-chain acetyl/ester moiety (C1), spiro-fused cyclopentanone (C2) and cyclohexanone (C3) rings, and 7-chloro (C4) and 7-bromo (C5) substituents, were evaluated in silico as potential COX-2 inhibitors. Molecular docking was performed with AutoDock Vina implemented in PyRx 0.8 against the crystal structure of human COX-2 co-crystallized with rofecoxib (PDB ID: 5KIR), using celecoxib as the reference inhibitor. All compounds displayed negative binding free energies (−6.7 to −7.3 kcal/mol), confirming spontaneous accommodation within the COX-2 active site, although none exceeded celecoxib (−7.9 kcal/mol). Compound C4 (7-chloro derivative) showed the highest affinity among the series (−7.3 kcal/mol) and the richest interaction network (LEU472, MET471, PRO86, SER119, LYS83, VAL89, TYR355, VAL116, LEU93). Compound C2 (−7.0 kcal/mol) uniquely engaged in a π–π T-shaped interaction with TYR115. Compounds C1, C3 and C5 shared an identical score (−6.7 kcal/mol), stabilized mainly via π-alkyl contacts with VAL89, VAL116 and LEU93. These results establish a preliminary structure-activity relationship in which halogenation and spiro-ring fusion enhance ligand accommodation within the COX-2 pocket, with C4 emerging as the most promising candidate for further experimental validation.