Drug Repurposing for Covid-19: Discovery of Potential Small-Molecule Inhibitors of Spike Protein-ACE2 Receptor Interaction Through Virtual Screening and Consensus Scoring

Sachin Patil, Jeremy Hofer, Pedro J. Ballester, Elena Fattakhova, Juliette DiFlumeri, Autumn Campbell, Michael Oravic

10.26434/chemrxiv.12482435.v1

Research curated

Abstract

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.

Source: ChemRxiv

Related molecules

Name	Synonyms	Genes
Angiotensin-converting enzyme 2-Spike glycoprotein interface
Tipranavir
Saquinavir
Maraviroc
Grazoprevir	Grazoprevir,1350514-68-9,MK5172,UNII-8YE81R1X1J, MK 5172
Simeprevir	Olysio, TMC435350, TMC-435, TMC435
Atazanavir
Telaprevir

Related interactions

Target	Drug	Type	Result
Angiotensin-converting enzyme 2-Spike glycoprotein interface	Atazanavir	Computational	positive
Angiotensin-converting enzyme 2-Spike glycoprotein interface	Grazoprevir	Computational	positive
Angiotensin-converting enzyme 2-Spike glycoprotein interface	Saquinavir	Computational	positive
Angiotensin-converting enzyme 2-Spike glycoprotein interface	Simeprevir	Computational	positive
Angiotensin-converting enzyme 2-Spike glycoprotein interface	Telaprevir	Computational	positive
Angiotensin-converting enzyme 2-Spike glycoprotein interface	Tipranavir	Computational	positive
Angiotensin-converting enzyme 2-Spike glycoprotein interface	Maraviroc	Computational	positive