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Covid19_Patil SP_v1.pdf (27.43 MB)
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Drug Repurposing for Covid-19: Discovery of Potential Small-Molecule Inhibitors of Spike Protein-ACE2 Receptor Interaction Through Virtual Screening and Consensus Scoring

preprint
submitted on 15.06.2020 and posted on 17.06.2020 by Sachin Patil, Jeremy Hofer, Pedro J. Ballester, Elena Fattakhova, Juliette DiFlumeri, Autumn Campbell, Michael Oravic

Objective

There is an increased interest in drug repurposing against Covid-19 (SARS-CoV-2) as its spread has significantly outpaced development of effective therapeutics. Our aim is to identify approved drugs that can inhibit the interaction of SARS-CoV-2 spike protein with human angiotensin-converting enzyme 2 (ACE2) that is critical for coronavirus infection.

Methods

The published crystal structure of SARS-CoV-2 spike protein-ACE2 receptor interaction was first analyzed for druggable binding pockets. The binding interface was then probed by an integrated virtual screening protocol executed by a high-performance computer cluster, involving docking and consensus scoring using various machine-learning, empirical and knowledge-based scoring functions. The consensus-ranked lists of screened drugs were generated via ‘rank-by-rank’ and ‘rank-by-number’ schemes.

Findings

Although spike protein and ACE2 lacked druggable pockets in their unbound forms, they presented a well-defined pocket when bound together. Accordingly, we identified many drugs with high binding potential against this protein-protein interaction pocket. Importantly, several antivirals against two major (+)ssRNA viruses (HCV and HIV) constituted major group of our top hits, of which Atazanavir, Grazoprevir, Saquinavir, Simeprevir, Telaprevir and Tipranavir could be of most importance for immediate experimental/clinical investigations. Additional notable hits included many anti-inflammatory/antioxidant, antibiotic/antifungal, and other relevant compounds with proven activity against respiratory diseases, further emphasizing robustness of our current study. Notably, we also discovered Maraviroc, the only FDA-approved drug capable of targeting virus-host interaction and blocking HIV entry.

Conclusion

Our newly identified compounds warrant further experimental investigation against SARS-CoV-2 spike-ACE2 interaction, which if proven effective may present much-needed immediate clinical potential against Covid-19.

History

Email Address of Submitting Author

spatil@widener.edu

Institution

Widener University

Country

USA

ORCID For Submitting Author

https://orcid.org/0000-0002-1354-0386

Declaration of Conflict of Interest

The authors declare no conflict of interest.

Version Notes

Version 1 (Manuscript Date 05/31/2020)

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