Repositioning of anti-dengue compounds against SARS-CoV-2 as viral polyprotein processing inhibitor

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 (Mpro), 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 Mpro 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 Mpro 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 Mpro. This study identified the top five compounds (CHEMBL1940602, CHEMBL2036486, CHEMBL3628485, CHEMBL200972, CHEMBL2036488) that showed a high affinity to Mpro with a docking score > -10.0 kcal/mol. The best-docked pose of these compounds with Mpro was subjected to 100 ns molecular dynamic (MD) simulation followed by MM/GBSA binding energy. This showed the maximum stability and comparable ΔG binding energy against the reference compound (X77 inhibitor). Overall, we repurposed the reported anti-dengue compounds against SARS-CoV-2-Mpro to impede its polyprotein processing for inhibiting SARS-CoV-2 infection.