2,3-Diarylindoles as COX-2 Inhibitors: Exploring the Structure-activity Relationship through Molecular Docking Simulations

Background: Arylindole derivatives are promising scaffolds in the design of new drugs, including inhibition of COX-2, antitumor activity, receptor GABA agonism, and estrogenic receptor modulation. Objective: Taking this into account, this paper presents a study to better understand the inhibitory action of certain 2-arylindole derivatives, specifically a series of 2,3-diarylindoles with IC50 values from 0.006 nM to 100 nM on the COX-2 enzyme and supports its structural-activity relationship (SAR) through molecular docking simulations. Methods: Briefly, the ligands’ three-dimensional models were drawn, and the conformational analysis was accessed in the Chem3D 19.1 program (PerkinElmer). After different steps of parametrizations, the lowest energy conformations were selected for the molecular docking simulation, which used the crystal structure of human COX-2 in complex with meclofenamic acid to 2.4 Å resolution (PDB code 5IKQ) as molecular target. Results: The results indicated that Gly 526 and Phe 381 residues are relevant for the improvement of inhibitory activity on para-substituted 3-phenyl- compounds. Arg 120 was also demonstrated to be an important residue for COX-2 inhibition, since it is involved in enabling a π-cation interaction with the best compound in series A5 (experimental IC50 = 0.006 nM determined in advance). Furthermore, COX-2 presents flexibility in some regions of the active site to adequately accommodate 5-substituted compounds containing an indole ring. Conclusion: Such structural features can be used as support for further Structural-Based Drug Design (SBDD) and/or Ligand-Based Drug Design (LBDD) studies of new selective COX-2 inhibitors.