Abstract
A therapy for COVID-19 (Coronavirus Disease 19) caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) remains elusive due to the lack of an effective antiviral therapeutic molecule. The SARS-CoV-2 main protease (M-pro), which plays a vital role in the viral life cycle, is one of the most studied and validated drug targets. In Several prior studies, numerous possible chemical entities were proposed as potential M-pro inhibitors; however, most failed at various stages of drug discovery. Repositioning of existing antiviral compounds accelerates the discovery and development of potent therapeutic molecules. Hence, this study examines the applicability of anti-dengue compounds against the substrate binding site of M-pro for disrupting its polyprotein processing mechanism. An in-silico structure-based virtual screening approach is applied to screen 330 experimentally validated anti-dengue compounds to determine their affinity to the substrate binding site of M-pro. This study identified the top five compounds (CHEMBL1940602, CHEMBL2036486, CHEMBL3628485, CHEMBL200972, CHEMBL2036488) that showed a high affinity to M-pro with a docking score > -10.0 kcal/mol. The best-docked pose of these compounds with M-pro was subjected to 100 ns molecular dynamic (MD) simulation followed by MM/GBSA binding energy. This showed the maximum stability and comparable Delta G binding energy against the reference compound (X77 inhibitor). Overall, we repurposed the reported anti-dengue compounds against SARS-CoV-2-M-pro to impede its polyprotein processing for inhibiting SARS-CoV-2 infection.