US EPA

7427959 

Journal Article 

Denovo designing, retro-combinatorial synthesis, and molecular dynamics analysis identify novel antiviral VTRM1.1 against RNA-dependent RNA polymerase of SARS CoV2 virus 

Tiwari, V 

2021 

Yes 

International Journal of Biological Macromolecules
ISSN: 0141-8130
EISSN: 1879-0003 

Elsevier B.V. 

171 

358-365 

English 

10.1016/j.ijbiomac.2020.12.223 

A novel coronavirus disease (COVID-19) caused by SARS-CoV2 has now spread globally. Replication/transcription machinery of this virus consists of RNA-dependent RNA polymerase (nsp12 or RdRp) and its two cofactors nsp7 and nsp8 proteins. Hence, RdRp has emerged as a promising target to control COVID-19. In the present study, we are reporting a novel inhibitor VTRM1.1 against the RdRp protein of SARS CoV2. A series of antivirals were tested for binding to the catalytic residues of the active site of RdRp protein. In-silico screening, molecular mechanics, molecular dynamics simulation (MDS) analysis suggest ribavirin, and remdesivir have good interaction with the binding site of the RdRp protein as compared to other antiviral investigated. Hence, ribavirin and remdesivir were used for the denovo fragments based antiviral design. This design, along with docking and MDS analysis, identified a novel inhibitor VTRM1 that has better interaction with RdRp as compared to their parent molecules. Further, to produce a lead-like compound, retrosynthetic analysis, and combinatorial synthesis were performed, which produces 1000 analogs of VTRM1. These analogs were analysed by docking and MDS analysis that identified VTRM1.1 as a possible lead to inhibit RdRp protein. This lead has a good docking score, favourable binding energy and bind at catalytic residues of the active site of RdRp. The VTRM1.1 also interacts with RdRp in the presence of RNA primer and other cofactors. It was also seen that, VTRM1.1 do not have off-target in human. Therefore, the present study suggests a hybrid inhibitor VTRM1.1 for the RNA-dependent RNA polymerase of SARS CoV2 that may be useful to control infection caused by COVID-19. © 2021 Elsevier B.V. 

Denovo designed antiviral; Molecular dynamics simulation; Retrosynthetic analysis; RNA-dependent RNA polymerase (RdRp); SARS-CoV2; 1 [4 [(4a hydroxy decahydroisoquinolin 2 yl)methyl] 2 aminophenyl] 2 minoethyl n [3 cyclopropylimidazo[1,5 a]pyridin 1 yl]carbamate; antivirus agent; ascorbic acid; favipiravir; hydroxychloroquine; oseltamivir; remdesivir; ribavirin; ritonavir; RNA directed RNA polymerase; tenofovir; umifenovir; unclassified drug; viral protein; VTRM1.1 protein; antivirus agent; enzyme inhibitor; NSP12 protein, SARS-CoV-2; antiviral activity; Article; binding affinity; binding site; catalysis; computer model; drug approval; drug design; drug protein binding; drug screening; drug structure; drug synthesis; enzyme active site; enzyme inhibition; enzyme structure; Food and Drug Administration; molecular docking; molecular dynamics; nonhuman; protein targeting; Severe acute respiratory syndrome coronavirus 2; chemistry; drug design; enzymology; human; molecular dynamics; protein domain; synthesis; Antiviral Agents; Binding Sites; Coronavirus RNA-Dependent RNA Polymerase; COVID-19; Drug Design; Enzyme Inhibitors; Humans; Molecular Dynamics Simulation; Protein Domains; SARS-CoV-2