A Virtual Docking Screen at 23 SARS‐CoV‐2 Proteins Identifies Drug Repurposing Candidates at New Sites and Targets

Olson, Keith; Chan, Wallace; Sexton, Jonathon; Carlson, Heather; Traynor, John

The ongoing severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) pandemic requires treatments with rapid clinical translatability. As such, several studies have screened FDA‐approved drugs in silico at a limited number of classical antiviral sites for anti‐SARS‐CoV‐2 activity. We hypothesized that an extensive in‐silico drug repurposingscreen against a wide range of SARS‐COV‐2 proteins could identify novel antiviral drugs and help elucidate mechanisms of drug action of hits from in vitro screens. We selected 48 known or predicted drug sites across 23 SARS‐COV‐2 proteins using homology models and crystal structures based on known antiviral drug sites (i.e., polymerase or protease active sites), computational predictions, and protein‐protein interfaces. Then, using the software GOLD, we docked 1268 FDA‐approved small‐molecule drugs into each site. Virtual hits were prioritized based on their anti‐SARS‐COV‐2 activity found in a recent phenotypic drug‐repurposing screen using human huh‐7 epithelial cells. This resulted in the identification of a range of drugs acting at a variety of targets and sites. Several compelling drug/site pairs were identified, including sites on the Spike protein, which mediates viral entry. For example, we identified hits with anti‐SARS‐CoV2 activity in vitro, at a putative allosteric site that incorporates two functionalities required for viral entry, namely the Spike S2’ cleavage site – which a host protease must cleave for viral entry, and the critical ‘fusion peptide’ domain – which injects itself into the host membrane during viral entry. Moreover, these in silico results identify possible mechanisms for in vitro drug repurposing hits, potential additional targets for known drugs, and a starting point to test drug combinations that may have better activity by acting at different steps in the viral cycle activity in combination than on their own. 8.5.5