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

Abstract

BACKGROUND\nThere 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.\n\n\nOBJECTIVE\nIn 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.\n\n\nMETHODS\nExtensive computational methods, such as virtual screening and molecular docking, were employed in this study.\n\n\nRESULTS\nTwo lead molecules- ZINC08825480 (4-bromo-N -{(E)-[1-phenyl-3-(pyridin-3-yl)-1H-pyrazol-4-yl]methylidene}benzene-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.\n\n\nCONCLUSION\nThus, the present study offers two novel chemical entities against coronavirus infections, which can be validated through various biological assays.