Identification of novel drug candidates for the inhibition of catalytic cleavage activity of coronavirus 3CL-like protease enzyme

Abstract

Background: There has been tremendous pressure on healthcare facilities globally due to the recent emergence of novel coronavirus infections known as COVID-19 and its rapid spread across the continents. The lack of effective therapeutics for the management of the pandemic calls for the discovery of new drugs and vaccines. Objective: In the present study, a chemical library was screened for molecules against three coronavirus 3CL-like protease enzymes (SARS-CoV-2 3CLpro, SARS-CoV 3CLpro and MERS-CoV 3CLpro), which are a key player in the viral replication cycle. Methods: Extensive computational methods, such as virtual screening and molecular docking, were employed in this study. Results: Two lead molecules- ZINC08825480 (4-bromo-N'-(E)-[1-phenyl-3-(pyridin-3-yl)-1H-pyrazol-4-yl]methylidenebenzene-1-sulfonohydrazide) and ZINC72009942 (N-[[2-[[(3S)-3-methyl-1-piperidyl]methyl]phenyl]methyl]-6-oxo-1-(p-tolyl)-4,5-dihydro-1,2,4-triazine-3-carboxamide) were identified with better affinity with the three target enzymes as compared to the approved antiviral drugs. Both the lead molecules possess favourable drug-like properties, fit well into the active site pocket close to His-Cys dyad and show a good number of hydrogen bonds with the backbone as well as side chains of key amino acid residues. Conclusion: Thus, the present study offers two novel chemical entities against coronavirus infections, which can be validated through various biological assays.