Fragment-based design of SARS-CoV-2 Mpro inhibitors.

ABSTRACT

The SARS-CoV-2 virus has been identified as a causative agent for COVID-19 pandemic. About more than 6.3 million fatalities have been attributed to COVID-19 worldwide to date. Finding a viable cure for the illness is urgently needed in light of the present pandemic. The prominence of main protease in the life cycle of virus shapes the main protease as a viable target for design and development of antiviral agents to combat COVID-19. The current study presents the fragment linking strategy to design the novel Mpro inhibitors for COVID-19. A total of 293,451 fragments from diversified libraries have been screened for their binding affinity towards Mpro enzyme. The best 1600 fragment hits were subjected to fragment joining to achieve 100 new molecules using Schrödinger software. The resulting molecules were further screened for their Mpro binding affinity, ADMET, and drug-likeness features. The best 13 molecules were selected, and the first 6 compounds were investigated for their ligand-receptor complex stability through a molecular dynamics study using GROMACS software. The resulting molecules have the potential to be further evaluated for COVID-19 drug discovery.