Abstract
The inhibition of key enzymes that may contain the viral replication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have assumed central importance in drug discovery projects. Nonstructural proteins (nsps) are essential for RNA capping and coronavirus replication since it protects the virus from host innate immune restriction. In particular, nonstructural protein 16 (nsp16) in complex with nsp10 is a Cap-0 binding enzyme. The heterodimer formed by nsp16-nsp10 methylates the 5′-end of virally encoded mRNAs to mimic cellular mRNAs and thus it is one of the enzymes that is a potential target for antiviral therapy. In this study, we have evaluated the mechanism of the 2′-O methylation of the viral mRNA cap using hybrid quantum mechanics/molecular mechanics (QM/MM) approach. It was found that the calculated free energy barriers obtained at M062X/6-31+G(d,p) is in agreement with experimental observations. Overall, we provide a detailed molecular analysis of the catalytic mechanism involving the 2′-O methylation of the viral mRNA cap and, as expected, the results demonstrate that the TS stabilization is critical for the catalysis.
Highlights
In September 2021, the World Health Organization (WHO) reported over 220 million cases of COVID-19 and over four million fatalities since the beginning of the pandemic [1].COVID-19 is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which is an enveloped β-coronavirus with a large, complex positive-sense single-strandedRNA genome [2]
Benoni et al [19] showed that nsp16-nsp10 complex can methyl-ate the first guanosine-50 -triphosphate (GTP) nucleobase of pre-capped mRNA, which is the natural substrate of nsp14
We have used quantum mechanics/molecular mechanics (QM/MM) approach to evaluate the reaction mechanisms of the mRNA cap catalyzed by 20 -O methyltransferase
Summary
COVID-19 is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which is an enveloped β-coronavirus with a large, complex positive-sense single-stranded. Coronaviruses have one of the largest genomes of all RNA viruses. The genome of SARS-CoV-2 has ~29,800 bases, which encodes four structural and 16 nonstructural proteins (nsp1-nsp16) that are essential for the lifecycle of this virus [3,4]. Inhibitors of the SARS-CoV-2 virus can be developed for particular targets that play important roles in viral replication. Most eukaryotic cellular and viral mRNAs are modified by the addition of a polyadenine tail at the 30 -terminal and a cap structure at the 50 -end.
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