ABSTRACT
Global health care emergency caused by a new coronavirus (severe acute respiratory syndrome coronavirus 2 or SARS-CoV-2) demands urgent need to repurpose the approved pharmaceutical drugs. Main protease, Mpro of SARS-CoV-2 draws significant attention as a drug target. Herein, we have screened FDA approved organosulfur drugs (till 2016) and our laboratory synthesized organosulfur and organoselenium compounds (L1-L306) against Mpro-apo using docking followed by classical MD simulations. Additionally, a series of compounds (L307-L364) were chosen from previous experimental studies, which were reported to exhibit inhibitory potentials towards Mpro. We found several organosulfur drugs, particularly Venetoclax (FDA approved organosulfur drug for Leukemia) to be a high-affinity binders to the Mpro of SARS-CoV-2. The results reveal that organosulfur compounds including Venetoclax preferentially bind (non-covalently) to the non-catalytic pocket of the protein located in the dimer interface. We found that the ligand binding is primarily favoured by ligand-protein van der Waals interaction and penalized by desolvation effect. Interestingly, Venetoclax binding alters the local flexibility of Mpro and exerts pronounced effect in the C-terminal as well as two loop regions (Loop-A and Loop-B) that play important roles in catalysis. These findings highlighted the importance of drug repurposing and explored the non-catalytic pockets of Mpro in combating COVID-19 infection in addition to the importance of catalytic binding pocket of the protein.Communicated by Ramaswamy H. Sarma.