Open Science Discovery of Potent Non-Covalent SARS-CoV-2 Main Protease Inhibitors
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Abstract
We report the results of the COVID Moonshot , a fully open-science, crowd sourced, structure-enabled drug discovery campaign targeting the SARS-CoV-2 main protease. We discovered a non-covalent, non-peptidic inhibitor scaffold with lead-like properties that is differentiated from current main protease inhibitors. Our approach leveraged crowdsourcing, machine learning, exascale molecular simulations, and high-throughput structural biology and chemistry. We generated a detailed map of the structural plasticity of the SARS-CoV-2 main protease, extensive structure-activity relationships for multiple chemotypes, and a wealth of biochemical activity data. All compound designs (>18,000 designs), crystallographic data (>840 ligand-bound X-ray structures), assay data (>10,000 measurements), and synthesized molecules (>2,400 compounds) for this campaign were shared rapidly and openly, creating a rich open and IP-free knowledgebase for future anti-coronavirus drug discovery.
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SciScore for 10.1101/2020.10.29.339317: (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 Percentage conversion (product peak integral / (product peak integral + substrate peak integral))*100) and percentage inhibitions were calculated and normalised against DMSO control with deduction of any background signal in Microsoft Excel. Microsoft Excelsuggested: (Microsoft Excel, RRID:SCR_016137)IC50s were calculated using Levenberg-Marquardt algorithm used to fit a restrained Hill equation to the dose-response data with both GraphPad PRISM and CDD. 1.4 Saturation Transfer Difference NMR (STD-NMR) assay: Method described in Kantsadi and Vakonakis [5]. GraphPad PRISMsuggested: (GraphPad …SciScore for 10.1101/2020.10.29.339317: (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 Percentage conversion (product peak integral / (product peak integral + substrate peak integral))*100) and percentage inhibitions were calculated and normalised against DMSO control with deduction of any background signal in Microsoft Excel. Microsoft Excelsuggested: (Microsoft Excel, RRID:SCR_016137)IC50s were calculated using Levenberg-Marquardt algorithm used to fit a restrained Hill equation to the dose-response data with both GraphPad PRISM and CDD. 1.4 Saturation Transfer Difference NMR (STD-NMR) assay: Method described in Kantsadi and Vakonakis [5]. GraphPad PRISMsuggested: (GraphPad Prism, RRID:SCR_002798)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: An explicit section about the limitations of the techniques employed in this study was not found. We encourage authors to address study limitations.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: We did not find any issues relating to colormaps.
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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