Targeting SARS-CoV-2 Main Protease: A Successful Story Guided by an <i>In Silico</i> Drug Repurposing Approach
Francesca Alessandra Ambrosio, Giosuè Costa, Isabella Romeo, Francesca Esposito, Mohammad Alkhatib, Romina Salpini, Valentina Svicher, Angela Corona, Paolo Malune, Enzo Tramontano, Francesca Ceccherini‐Silberstein, Stefano Alcaro, Anna Artese
Abstract
The SARS-CoV-2 main protease (M pro ) is a crucial enzyme for viral replication and has been considered an attractive drug target for the treatment of COVID-19. In this study, virtual screening techniques and in vitro assays were combined to identify novel M pro inhibitors starting from around 8000 FDA-approved drugs. The docking analysis highlighted 17 promising best hits, biologically characterized in terms of their M pro inhibitory activity. Among them, 7 cephalosporins and the oral anticoagulant betrixaban were able to block the enzyme activity in the micromolar range with no cytotoxic effect at the highest concentration tested. After the evaluation of the degree of conservation of M pro residues involved in the binding with the studied ligands, the ligands’ activity on SARS-CoV-2 replication was assessed. The ability of betrixaban to affect SARS-CoV-2 replication associated to its antithrombotic effect could pave the way for its possible use in the treatment of hospitalized COVID-19 patients.