RR:C19 Evidence Scale rating by reviewer:
Reliable. The main study claims are generally justified by its methods and data. The results and conclusions are likely to be similar to the hypothetical ideal study. There are some minor caveats or limitations, but they would/do not change the major claims of the study. The study provides sufficient strength of evidence on its own that its main claims should be considered actionable, with some room for future revision.
The manuscript entitled “Identification of 14 Known Drugs as Inhibitors of the Main Protease of SARS-CoV-2” is a novel topic that will be of interest to the readers. Ghahremanpour et.al. summarize in this paper, the current status in the potential development of drugs against COVID-19 specifically targeting Main Protease enzyme. The article gives an interesting scientific perspective on a field that has only recently boomed; focusing mostly on the pipeline that most of the bioinformaticians/data scientists do to investigate or repurpose drugs against a specific disease for instance COVID-19 in this case. It is a well-written, needed, and useful summary of the current status of the pandemic from a certain perspective. The authors, however, need to be bolder and more analytical. This is an opinion piece, yet I see little opinion. A certain view is implied by the organization of the paper and the references chosen, but they could be more explicit. With modifications addressing the detailed comments below and better recognizing the complexity of the current data publication landscape, this will be a worthwhile research paper. With more significant modification where the authors dig deeper into the complexities and controversies and truly grapple with their implications to suggest a way forward, this could be a very influential paper. It is possible that the definitions of “publication” and “peer-review” need not be just stretched but changed or even rejected.
In the Abstract, authors should clarify the term “ca.” used in the first sentence.
A study has been published in Science Advances recently by Panda et.al addressing virtual screening pipeline. It would be good to cite this reference as they have a similar approach to your study.
The authors have targeted the active site during grid selection in molecular docking. Is there a specific reason to do that? I think it would be better to have a report on blind docking (setting grid for the whole protein) to compare the results with the active site docking.
Why the authors have chosen OPLS-AA/M forcefield for protein-ligand simulation? Please justify?
Authors should give a 2D plot (Discovery studio 2D plot or LigPlot) of the bonding patterns derived from the interactions of the drug compounds against Mpro (As a supplementary information).
Did the authors check the interactions of the drug compounds after the simulation? Do all the selected drugs retain their position or interacted with the active site residues? Please provide 2D plots for the same in supplementary information.
70ns is very specific. Either you perform 50ns or 100ns if you are going for longer time scale more than 10ns. Why so specific?
A constructive conclusion can be derived through this study as the 5 compounds identified are very much similar to the symptoms observed in COVID-19 case e.g. calcium channel blocker which reduces the blood pressure and they are protease
inhibitors. A significant analysis has been depicted in this study and may be as authors stated that all these compounds warrant further extensive studies.
The readers would benefit from a more in-depth discussion of the challenges you faced in implementing your project and how you overcame these barriers.
What suggestions do you have for the researchers who would like to replicate your project? Authors need to be more forthright saying what drug repurposing means or what parts of it they do not deal with.
The paper would be both more compelling and useful to a broad readership if the authors moved beyond providing a simple summary of the concluding remarks and examined why there is need of such studies during this pandemic or any future events and then use the evidence they have compiled to suggest a path forward.
Overall though, this is a timely and needed research.