High-throughput rational design of the remdesivir binding site in the RdRp of SARS-CoV-2: implications for potential resistance
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SciScore for 10.1101/2020.06.27.174896: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
NIH rigor criteria are not applicable to paper type.Table 2: Resources
Software and Algorithms Sentences Resources Molecular docking was performed using the AutoDock Tools to dock the EIDD-2801 into the nsp12 binding cavity, in which it exerts its antiviral action via the introduction of copying errors during viral RNA replication (28, 29). AutoDocksuggested: (AutoDock, RRID:SCR_012746)Occurrence of mutations in top-ranked affinity-enhanced and affinity-attenuated designs: The type and frequency of designed amino acids in the 56 and 65 nsp12-interacting residues of Remdesivir and EIDD-2801, respectively, from the top-ranked affinity-enhanced and affinity-attenuated designs were obtained and plotted … SciScore for 10.1101/2020.06.27.174896: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
NIH rigor criteria are not applicable to paper type.Table 2: Resources
Software and Algorithms Sentences Resources Molecular docking was performed using the AutoDock Tools to dock the EIDD-2801 into the nsp12 binding cavity, in which it exerts its antiviral action via the introduction of copying errors during viral RNA replication (28, 29). AutoDocksuggested: (AutoDock, RRID:SCR_012746)Occurrence of mutations in top-ranked affinity-enhanced and affinity-attenuated designs: The type and frequency of designed amino acids in the 56 and 65 nsp12-interacting residues of Remdesivir and EIDD-2801, respectively, from the top-ranked affinity-enhanced and affinity-attenuated designs were obtained and plotted using WebLogo, which graphically represents the multiple sequence alignment of an amino acid profile (33). WebLogosuggested: (WEBLOGO, RRID:SCR_010236)Calculation of intermolecular interactions between Remdesivir- and EIDD-2801-bound nsp12 designs in the affinity-enhancing and affinity-attenuating mutants: The intermolecular interactions between top-ranked affinity-enhancing and affinity-attenuating Remdesivir-nsp12 and EIDD-2801-nsp12 designs were obtained using the Arpeggio webserver (36). Arpeggiosuggested: (Arpeggio, RRID:SCR_010876)Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).
Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:We acknowledge certain limitations in the current study. Our Rosetta ligand-based interface design method (and scoring function) is set to design mutants with improved interface delta and therefore increased binding affinity to Remdesivir. However, ideally, the Remdesivir-resistance mutations are affinity-attenuating designs. To the best of our knowledge, at present, neither Rosetta nor any other programs have protocols to accurately score and predict affinityattenuating designs to correlate with a drug resistance mutation. Nonetheless, Rosetta methodology remains the only useful design-based tool for mutational mapping and prediction of specific residues involved in enhancing or attenuating protein-ligand interaction. Therefore, to make sure that our Rosetta protocol captures the correct affinity-attenuating designs to correlate with Remdesivir-resistance mutations, we carried out control experiments by taking the wild-type and a previously known Remdesivir-resistance SARS-CoV mutation as control. We argue that the affinity-attenuating designs representing the potential hotspot residues have a higher probability of undergoing selective mutations in the future to develop Remdesivir and related drug-based resistance. Finally, owing to a lack of the structure of the RdRp-EIDD-2801 complex, the exact structural information predicted from the docked complex of RdRp-EIDD-2801 might not be precise; however, since Remdesivir and EIDD-2801 bind at the same position, the error might n...
Results from TrialIdentifier: No clinical trial numbers were referenced.
Results from Barzooka: We did not find any issues relating to the usage of bar graphs.
Results from JetFighter: Please consider improving the rainbow (“jet”) colormap(s) used on pages 20 and 21. At least one figure is not accessible to readers with colorblindness and/or is not true to the data, i.e. not perceptually uniform.
Results from rtransparent:- Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
- No funding statement was detected.
- No protocol registration statement was detected.
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