ABSTRACT
Mitigation of the activity of the main protease (Mpro) and papain-like protease (PLpro) of SARS CoV-2 has direct implications in combating the ongoing deadly COVID-19 pandemic. The active site of these proteases contains cysteine thiols which are covalently modified by the sulfur drugs such as ebselen and disulfiram. The natural product of Allium contains several reactive sulfur compounds that may covalently modify the active site cysteine thiols of coronavirus proteases. The report has assessed the binding affinity of the 52 different sulfur compounds of Allium against both Mpro and PLpro of coronavirus by conventional docking methods. Three of the top six compounds have demonstrated high affinity for both the proteases, namely, E-ajoene (S3), S-(3-pentanyl)-L-cysteine-sulfoxide (S49), and 1-propenyl allyl thiosulfinate (S14). The reactive sulfur compounds E-ajoene and 1-propenyl allyl thiosulfinate were subjected to the calculation of energetics of the putative reactions and covalent docking studies. The results indicate they covalently modify the active site cysteine thiols of the proteases through S-thioallylation, S-thioallyl sulfinyl propenylation, and S-thiopropenylation. The diversity of covalent modifications, high affinity for both the proteases and sulfur-mediated hydrogen bonds at the active site indicate that E-ajoene is a potential dual protease targeting covalent inhibitor of SARS CoV-2.