Repurposing of Drugs for SARS-CoV-2 Using Inverse Docking Fingerprints

Severe acute respiratory syndrome coronavirus 2 or SARS-CoV-2 is a virus that belongs to the Coronaviridae family. This group of viruses commonly causes colds but possesses a tremendous pathogenic potential. In humans, an outbreak of SARS caused by the SARS-CoV virus was first reported in 2003, followed by 2012 when the Middle East respiratory syndrome coronavirus (MERS-CoV) led to an outbreak of Middle East respiratory syndrome (MERS). Moreover, COVID-19 represents a serious socioeconomic and global health problem that has already claimed more than four million lives. To date, there are only a handful of therapeutic options to combat this disease, and only a single direct-acting antiviral, the conditionally approved remdesivir. Since there is an urgent need for active drugs against SARS-CoV-2, the strategy of drug repurposing represents one of the fastest ways to achieve this goal. An in silico drug repurposing study using two methods was conducted. A structure-based virtual screening of the FDA-approved drug database on SARS-CoV-2 main protease was performed, and the 11 highest-scoring compounds with known 3CL^pro activity were identified while the methodology was used to report further 11 potential and completely novel 3CL^pro inhibitors. Then, inverse molecular docking was performed on the entire viral protein database as well as on the Coronaviridae family protein subset to examine the hit compounds in detail. Instead of target fishing, inverse docking fingerprints were generated for each hit compound as well as for the five most frequently reported and direct-acting repurposed drugs that served as controls. In this way, the target-hitting space was examined and compared and we can support the further biological evaluation of all 11 newly reported hits on SARS-CoV-2 3CL^pro as well as recommend further in-depth studies on antihelminthic class member compounds. The authors acknowledge the general usefulness of this approach for a full-fledged inverse docking fingerprint screening in the future.