Several possible drug targets have been identified against severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) by taking insights into the life cycle of virus in order to design inhibitor compounds. Chymotrypsin-like (3CL) protease, which is also known as main protease, by undergoing self-cleavage causes post-translational modifications of viral polyprotein to generate non-structural proteins (nsp1-nsp16), which is essential for viral replication process. Inhibition of main protease halts the viral replication process and thus, inhibits the viral maturation. Main protease being a cysteine protease is susceptible to covalent inhibition through Cis-His catalytic dyad, that act as site for covalent bond formation. In this work, a virtual library of 23,700 nitreone-peptide hybrids was prepared, which was consisted of 79 nitreones and 300 peptide frameworks. High throughput virtual screening resulted 4700 molecules having HTVS docking score better than co-crystalized ligand N3. Standard precision (SP) docking of 4700 molecules followed by extra precision docking of top 20% molecules resulted 36 top scoring compound with XP docking score better than that of N3 (-10.0). SP and XP docking were conducted in triplicate. Covalent docking on top 20 compounds and molecular dynamic simulation on top scoring four molecules resulted the more promising irreversible inhibitor of main protease than N3.

<i>In silico </i>design of nitreone-peptide hybrids as irreversible inhibitors of SARS-CoV-2 main protease

ACS Fall 2021

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In silico design of nitreone-peptide hybrids as irreversible inhibitors of SARS-CoV-2 main protease