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

pbObjective/b/pp /ppThere 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 /pp /ppbMethods/b/pp /ppThe 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 /pp /ppbFindings/b/pp /ppAlthough 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 /pp /ppbConclusion/b/pp /pOur 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