A Drug Repurposing Approach to Identify Therapeutics by Screening Pathogen Box Exploiting SARS‐CoV‐2 Main Protease

Abstract

AbstractCoronavirus disease‐19 (COVID‐19) is caused by severe acute respiratory syndrome coronavirus ‐2 (SARS‐CoV‐2) and is responsible for a higher degree of morbidity and mortality worldwide. There is a smaller number of approved therapeutics available to target the SARS‐CoV‐2 virus, and the virus is evolving at a fast pace. So, there is a continuous need for new therapeutics to combat COVID‐19. The main protease (Mpro) enzyme of SARS‐CoV‐2 is essential for replication and transcription of the viral genome, thus could be a potent target for the treatment of COVID‐19. In the present study, we performed an in‐silico screening analysis of 400 diverse bioactive inhibitors with proven antibacterial and antiviral properties against Mpro drug target. Ten compounds showed a higher binding affinity for Mpro than the reference compound (N3), with desired physicochemical properties. Furthermore, in‐depth docking and superimposition revealed that three compounds (MMV1782211, MMV1782220, and MMV1578574) are actively interacting with the catalytic domain of Mpro. In addition, the molecular dynamics simulation study showed a solid and stable interaction of MMV178221‐Mpro complex compared to the other two molecules (MMV1782220, and MMV1578574). In line with this observation, MM/PBSA free energy calculation also demonstrated the highest binding free energy of −115.8 kJ/mol for MMV178221‐Mpro compound. In conclusion, the present in silico analysis revealed MMV1782211 as a possible and potent molecule to target the Mpro and must be explored in vitro and in vivo to combat the COVID‐19.