Potential Drugs Targeting Early Innate Immune Evasion of SARS-Coronavirus 2 via 2’-O-Methylation of Viral RNA

Round 1

Reviewer 1 Report

The authors have used a molecular docking approach to characterize a series of small molecule inhibitors for their ability to block the interaction between to coronavirus-specific proteins nsp10 and nsp16 in order to block its biological function.  The protein interaction is important for the viral life cycle as it is responsible for capping the mRNA of the virus.  The authors target three regions of the interacting proteins, the docking site, the SAM binding site, and the RNA binding site to increase the likelihood of identifying relevant inhibitors.  The approach is logical and the authors have adequately described their results both from the perspective of the docking calculations as well as from the perspective of the nature of the small molecule inhibitors.  The major shortcoming of this study is the absence of any biochemical evidence to suggest that any of the identified inhibitors actually might work to block the function of the  nsp10 and nsp16 combination.  

Author Response

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Reviewer 2 Report

The pandemic of COVID-19 is still rampant worldwide, and anti-SARS-CoV-2 drug is urgently desired. This work reported that using a molecular docking-based virtual screening for drug repurposing against SARS-CoV-2 infection, from ~9,000 drugs. The targets for molecular docking are based on three differential traits of the inter-molecular interactions of the SARS-CoV- 2-specific nsp16/nsp10. Basically, this work is well done, but many descriptions are too tediously long. Especially the Introduction and Discussion should be cut to a more concise text.

One concern is that in their results, more than 10 predicted drugs were thought as candidate drugs against SARS-CoV-2, but there is lack of any experimental data with in vitro cell model or animal in vivo data, so it is hard to predict which one is the best candidate for the next study? At least, the authors should declare that their prediction is too wide for the next validation.

Figure 1 and Figure 2 have some repetitive and non-substantive information, and it should be re-organized and merged.

Author Response

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Author Response File: Author Response.docx

Round 2

Reviewer 2 Report

The author have addressed my concerns.