Computational Screening for Finding New Potent COX-2 Inhibitors as Anticancer Agents

Background: Breast cancer ranks first in women and is the second most common type of cancer overall. It is the most important barrier to the rise of life expectancy, globally affecting disease modalities. Cyclooxygenase-2 (COX-2) has become a prominent hallmark as an inhibition target for breast cancer, and this therapeutic target for anti-inflammatory drugs regulates cell proliferation, angiogenesis, tumor growth and apoptosis. There is a need to explore new anti-cancerous drugs for searching the best possible hit candidates for cancer treatment. The computer-aided drug design approach was conducted to discover the new alternative COX-2 inhibitors. Objective: The research framework of this study is to identify new potent inhibitors for the COX-2 receptor using computer-aided drug design. Methods: In the present investigation, an in-silico approach was used to screen with the best established three biological databases (Zinc15, ChemSpider and BindingDB) and docked against the COX-2 protein structure (PDB ID: 5IKR). Molecular docking was carried out using the Schrodinger Maestro suite. The compounds were filtered out based on their physicochemical, ADMET, and other drug-like properties. Several computational approaches such as molecular docking, binding free energy calculation, ADMET analysis, protein-ligand interaction and MD simulation were performed to determine the suitability of correct ligands for the selected COX-2 target. Results: The two ligands showed relatively better binding affinities (-10.028 kcal/mol for compound A and -10.007 kcal/mol for ZINC000048442590) than the standard (-9.751 kcal/mol). These compounds followed Lipinski’s rule and drug-likeness index, which exhibited a good predicted therapeutic druggability profile. The interaction of the protein-ligand complex correlates with the COX-2 receptor. The MD simulation of the protein-ligand complex showed good stability in the time period of 10ns. Conclusion: It is the first study in which two new compounds ZINC000048442590 and compound A were found to be highly promising with active potential in inhibiting cyclooxygenase-2 enzyme could be effective as the potential drug candidates for breast cancer against COX-2 protein. Hopefully, in the future, these compounds as anti-inflammatory drug molecules could be used as new templates for the development of anticancer agents.