PF-46396

Coronavirus 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.

HIV-1 Maturation inhibitors (MIs) bind to the C-terminal domain of capsid protein (CA-CTD) and spacer peptide 1 (SP1) in HIV-1 Gag and inhibit the CA-SP1 cleavage by stabilizing the immature Gag. The β-turn motif, GVGGP in the HIV CA-CTD (residues 220-224) is one of the key determinants of HIV Gag assembly. In the present study, we mutated each residue of HIV-1 β-turn motif to alanine and observed complete inhibition of virus release of all mutants. This defect in virus release was rescued in the presence of maturation inhibitors; BVM and PF-46396 for P224A mutant. To our knowledge, this is the first report of identification of BVM and PF-46396-dependent capsid mutant. Our results highlight the importance of the core β-turn motif residues in immature virus assembly and suggest that the presence of MIs enhances Gag membrane binding and multimerization thereby restoring virus release of HIV Gag P224 mutant.