ABSTRACT

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COVID-19 (SARS-CoV-2) is a novel betacoronavirus responsible for the infection of 89.5 million people worldwide as of January of 2021, attributing to a serious pandemic and quarantines. Upon cell entry, the SARS-CoV-2 virus replicates using single stranded positive sense RNA, which are translated into two large polyproteins. The virus relies on a viral main protease to activate these polyproteins into nonstructural proteins responsible for basic viral function. Inhibition of the viral main protease effectively arrests viral replication cycle. Thus, we designed and screened in silico a library of modified tripeptides containing a key Michael acceptor electrophilic trap seeking covalent inhibition of the main protease. The selection of electron withdrawing groups considers the relative rates of Michael additions between cysteine proteases and vinyl Michael acceptors, and the selection of amino acid side chains in the two unmodified peptides is based on electrostatic interactions with the main protease active site cysteine. Specifically, we utilized density-functional theory (DFT) to model 40 vinyl sulfonate ester-based Michael acceptors, of which 20 were screened through molecular docking to investigate the effects of a different electron withdrawing group on the binding affinity of our compounds to the SARS-CoV-2 main protease active site. We determined that vinyl sulfonate esters had, on average, superior binding affinity when compared to traditional amide-based Michael acceptors.