A comprehensive review on promising anti-viral therapeutic candidates identified against main protease from SARS-CoV-2 through various computational methods

Abstract

Background The COVID-19 pandemic caused by SARS-CoV-2 has shown an exponential trend of infected people across the planet. Crediting its virulent nature, it becomes imperative to identify potential therapeutic agents against the deadly virus. The 3-chymotrypsin-like protease (3CLpro) is a cysteine protease which causes the proteolysis of the replicase polyproteins to generate functional proteins, which is a crucial step for viral replication and infection. Computational methods have been applied in recent studies to identify promising inhibitors against 3CLpro to inhibit the viral activity. Main body of the abstract This review provides an overview of promising drug/lead candidates identified so far against 3CLpro through various in silico approaches such as structure-based virtual screening (SBVS), ligand-based virtual screening (LBVS) and drug-repurposing/drug-reprofiling/drug-retasking. Further, the drugs have been classified according to their chemical structures or biological activity into flavonoids, peptides, terpenes, quinolines, nucleoside and nucleotide analogues, protease inhibitors, phenalene and antibiotic derivatives. These are then individually discussed based on the various structural parameters namely estimated free energy of binding (ΔG), key interacting residues, types of intermolecular interactions and structural stability of 3CLpro-ligand complexes obtained from the results of molecular dynamics (MD) simulations. Conclusion The review provides comprehensive information of potential inhibitors identified through several computational methods thus far against 3CLpro from SARS-CoV-2 and provides a better understanding of their interaction patterns and dynamic states of free and ligand-bound 3CLpro structures.

Phytochemicals against SARS-CoV as potential drug leads

“…Notably, humans do not have a 3CL pro homologue. Thus, 3CL pro is an attractive target for COVID-19 antiviral drug development [ [16] , [17] , [18] ].

Figure 2 Schematic representation for the localization and function of possible inhibitor classes against 3CL pro from SARS-CoV-2 (Adopted from Singh et al [ 18 ]).

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“… Schematic representation for the localization and function of possible inhibitor classes against 3CL pro from SARS-CoV-2 (Adopted from Singh et al [ 18 ]). …”

Biochemical features and mutations of key proteins in SARS-CoV-2 and their impacts on RNA therapeutics

“…Based on analyses of structure characteristics of M pro and the free energy of binding between the active site and potential targeting compounds, in silico approaches including molecular docking can provide insights that lead to discovering new drug candidates or repurposing preexisting drugs. In silico studies suggested that many compounds exhibit inhibitory effects against M pro , and that these compounds include flavonoids, peptides, terpenes, quinolines, nucleoside or nucleotide analogues, conventional protease inhibitors, phenalene, antibiotic derivatives, imidazole, and indoles [26] . Biochemical high throughput screening (HTS) strategies have also been applied to screen synthetic or natural compounds.…”

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“…These values are lower than the binding energy obtained when we docked viomycin against the same amino acids, which stood at -3 kcal/mol. Viomycin is being actively pursued as a promising inhibitor of the SARS-CoV-2 main protease 25 , and the ability of the two Ocimum flavonoids to bind better to the critical active site amino acid residues of the main protease 21 holds promise for the two flavonoids to be checked more intensively. We docked the two flavonoids against the RNA-dependent RNA polymerase of the SARS-CoV-2 virus.…”