A Blueprint for High Affinity SARS-CoV-2 Mpro Inhibitors from Activity-Based Compound Library Screening Guided by Analysis of Protein Dynamics
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SciScore for 10.1101/2020.12.14.422634: (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 100 Druggability analysis of Sars-CoV2 main protease structure: The SiteMap tool,101 together with the TRAPP (TRAnsient Pockets in Proteins) approach42 were used for the characterization of the proteins’ binding sites. SiteMapsuggested: (Biositemaps, RRID:SCR_001976)104 All TRAPP analysis was conducted on homodimeric structures, generated with the symmetry wizard of PyMol. PyMolsuggested: (PyMOL, RRID:SCR_000305)All compounds46, 47, 52, 54, 56, 60–62, 65 were converted from 2D to 3D and prepared with Schrödinger’s LigPrep tool. Schrödinger’ssuggested: (Maestro, RRID:SCR_016748)LigPrepsuggeste…SciScore for 10.1101/2020.12.14.422634: (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 100 Druggability analysis of Sars-CoV2 main protease structure: The SiteMap tool,101 together with the TRAPP (TRAnsient Pockets in Proteins) approach42 were used for the characterization of the proteins’ binding sites. SiteMapsuggested: (Biositemaps, RRID:SCR_001976)104 All TRAPP analysis was conducted on homodimeric structures, generated with the symmetry wizard of PyMol. PyMolsuggested: (PyMOL, RRID:SCR_000305)All compounds46, 47, 52, 54, 56, 60–62, 65 were converted from 2D to 3D and prepared with Schrödinger’s LigPrep tool. Schrödinger’ssuggested: (Maestro, RRID:SCR_016748)LigPrepsuggested: (Ligprep, RRID:SCR_016746)Rigid-body docking was performed using OpenEye FRED,68, 115, 116 which is included in the OEDocking 3.4.0.2 suite.68, 115, 116 Each conformer was docked by FRED in the negative image of the active site of the target protein, which consists of a shape potential field in the binding site volume. OpenEyesuggested: (OpenEye, RRID:SCR_014880)The PLIF representation in the form of stacked histograms used in this work was generated using python matplotlib library (v 3.3.1). pythonsuggested: (IPython, RRID:SCR_001658)matplotlibsuggested: (MatPlotLib, RRID:SCR_008624)Scikit-learn t-SNE implementation with a custom Tanimoto distance metric was used (see supporting information) in an in-house python script. Scikit-learnsuggested: (scikit-learn, RRID:SCR_002577)Results from OddPub: Thank you for sharing your code and data.
Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:Within the limitations of the procedure (discussed in the Limitation paragraph), we obtained an “active-pharmacophore” that we first used against a selection of SARS-CoV-2 Mpro binders (46 molecules): the latter are very diverse and they are spread overall the t-SNE plot (Figure 7). The active-pharmacophore could predict known nM-binders for SARS-CoV-2 Mpro (12 molecules out of the total of 46), which are also clustered in the peptides and peptidomimetics region of the t-SNE plot, and discriminate these from the μM ones. Moreover, it could also discriminate the transferable from the non-transferable binding features from SARS-CoV to SARS-CoV-2 Mpro. The former include the interaction with the catalytic dyad residues along with: (i) His163, whose mutation to Ala inactivates SARS-CoV Mpro,91 (ii) Glu166, which plays a role in the dimerization (required for enzymatic activity) in SARS-CoV.92 In addition, its interactions with the N-finger of the other subunit assist the correct orientation of residues in the binding pocket for both proteins,92, 93 (iii) Gln189, which correlates evolutionally with residues from the Cys44-Pro52 loop in both proteins, which was shown to regulate ligand entrance to the binding site18 in both proteins, and (iv) Ser144, whose mutation to Ala hampers the catalytic activity in SARS-Cov MPro.94 The non-transferable binding features include the ability to place large hydrophobic/aromatic groups in the part of the cavity defined by Thr25 and Thr26 that is ...
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 page 3. 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.
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