A Repurposed Drug Screen Identifies Compounds That Inhibit the Binding of the COVID-19 Spike Protein to ACE2
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Abstract
Repurposed drugs that block the interaction between the SARS-CoV-2 spike protein and its receptor ACE2 could offer a rapid route to novel COVID-19 treatments or prophylactics. Here, we screened 2,701 compounds from a commercial library of drugs approved by international regulatory agencies for their ability to inhibit the binding of recombinant, trimeric SARS-CoV-2 spike protein to recombinant human ACE2. We identified 56 compounds that inhibited binding in a concentration-dependent manner, measured the IC 50 of binding inhibition, and computationally modeled the docking of the best inhibitors to the Spike-ACE2 binding interface. The best candidates were Thiostrepton, Oxytocin, Nilotinib, and Hydroxycamptothecin with IC50’s in the 4–9 μM range. These results highlight an effective screening approach to identify compounds capable of disrupting the Spike-ACE2 interaction, as well as identify several potential inhibitors of the Spike-ACE2 interaction.
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SciScore for 10.1101/2021.04.08.439071: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement not detected. Randomization not detected. Blinding not detected. Power Analysis not detected. Sex as a biological variable not detected. Table 2: Resources
Software and Algorithms Sentences Resources In Silico Modeling: The S1 subunit of SARS-CoV-2 spike protein comprising the receptor binding domain (RBD) was modelled using the SWISS-MODEL server11, the FASTA sequence (residues 316-530) was retrieved from UniProtKB - P0DTC2 and used as a query sequence, PDB ID: 6VSB with 100% sequence identity was used as a template12,13. UniProtKBsuggested: (UniProtKB, RRID:SCR_004426)The SDF structures of the selected FDA-approved drugs were downloaded from Selleck chemicals and PubChem. Pub…SciScore for 10.1101/2021.04.08.439071: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement not detected. Randomization not detected. Blinding not detected. Power Analysis not detected. Sex as a biological variable not detected. Table 2: Resources
Software and Algorithms Sentences Resources In Silico Modeling: The S1 subunit of SARS-CoV-2 spike protein comprising the receptor binding domain (RBD) was modelled using the SWISS-MODEL server11, the FASTA sequence (residues 316-530) was retrieved from UniProtKB - P0DTC2 and used as a query sequence, PDB ID: 6VSB with 100% sequence identity was used as a template12,13. UniProtKBsuggested: (UniProtKB, RRID:SCR_004426)The SDF structures of the selected FDA-approved drugs were downloaded from Selleck chemicals and PubChem. PubChemsuggested: (PubChem, RRID:SCR_004284)Ligand and protein preparation was performed using the Ligprep and protein preparation wizard tool on Schrödinger Maestro version 12.2. Maestrosuggested: (Maestro, RRID:SCR_016748)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.
- Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
- No protocol registration statement was detected.
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