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Repurposing nonnucleoside antivirals against SARS-CoV2 NSP12 (RNA dependent RNA polymerase): In silico-molecular insight.

ABSTRACT: The pandemic of SARS-CoV-2 has necessitated expedited research efforts towards finding potential antiviral targets and drug development measures. While new drug discovery is time consuming, drug repurposing has been a promising area for elaborate virtual screening and identification of existing FDA approved drugs that could possibly be used for targeting against functions of various proteins of SARS-CoV-2 virus. RNA dependent RNA polymerase (RdRp) is an important enzyme for the virus that mediates replication of the viral RNA. Inhibition of RdRp could inhibit viral RNA replication and thus new virus particle production. Here, we screened non-nucleoside antivirals and found three out of them to be strongest in binding to RdRp out of which two retained binding even using molecular dynamic simulations. We propose these two drugs as potential RdRp inhibitors which need further in-depth testing.

SUBMITTER: Begum F

PROVIDER: S-EPMC8282484 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:An outbreak of a cluster of viral pneumonia cases, subsequently identified as coronavirus disease 2019 (COVID-19), due to a novel SARS-CoV-2 necessitates an urgent need for a vaccine to prevent infection or an approved medication for a cure. In our in silico molecular docking study, a total of 173 compounds, including FDA-approved antiviral drugs, with good ADME descriptors, and some other nucleotide analogues were screened. The results show that these compounds demonstrate strong binding affinity for the residues at the active sites of RNA-dependent RNA-polymerase (RdRp) modelled structures and Chymotrypsin-like cysteine protease (3CLpro) of the HCoV proteins. Free energies (ΔG's) of binding for SARS-CoV-2 and SARS-CoV RdRp range from - 5.4 to - 8.8 kcal/mol and - 4.9 to - 8.7 kcal/mol, respectively. Also, SARS-CoV-2 and SARS-CoV 3CLpro gave ΔG values ranging from - 5.1 to - 8.4 kcal/mol and - 5.5 to - 8.6 kcal/mol, respectively. Interesting results are obtained for ivermectin, an antiparasitic agent with broad spectrum activity, which gave the highest binding energy value (- 8.8 kcal/mol) against the 3CLpro of SARS-CoV-2 and RdRps of both SARS-CoV and SARS-CoV-2. The reason for such high binding energy values is probably due to the presence of hydroxy, methoxy and sugar moieties in its structure. The stability of the protein-ligand complexes of polymerase inhibitors considered in this investigation, such as Sofosbuvir, Remdesivir, Tenofovir, Ribavirin, Galidesivir, 5c3, 5h1 and 7a1, show strong to moderate hydrogen bonding and hydrophobic interactions (π-π stacked, π-π T-shaped, π-sigma and π-alkyl). The stability provided from such interactions translate into greater antiviral activity or inhibitory effect of the ligands. Assessment of the average free energies of binding of the FDA approved drugs are highly comparable for conformers of a particular inhibitor, indicating similar modes of binding within the pockets.Supplementary informationThe online version contains supplementary material available at 10.1007/s13721-021-00299-2.

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Repurposing nonnucleoside antivirals against SARS-CoV2 NSP12 (RNA dependent RNA polymerase): In silico-molecular insight.

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