Targeting SARS-CoV-2: a systematic drug repurposing approach to identify promising inhibitors against 3C-like proteinase and 2′-O-ribose methyltransferase

Abstract

2020): Targeting SARS-CoV-2: a systematic drug repurposing approach to identify promising inhibitors against 3C-like proteinase and 2′-O-ribose methyltransferase, Journal of Biomolecular Structure and Dynamics, ABSTRACTThe recent pandemic associated with SARS-CoV-2, a virus of the Coronaviridae family, has resulted in an unprecedented number of infected people. The highly contagious nature of this virus makes it imperative for us to identify promising inhibitors from pre-existing antiviral drugs. Two druggable targets, namely 3C-like proteinase (3CLpro) and 2 0 -O-ribose methyltransferase (2 0 -O-MTase) were selected in this study due to their indispensable nature in the viral life cycle. 3CLpro is a cysteine protease responsible for the proteolysis of replicase polyproteins resulting in the formation of various functional proteins, whereas 2 0 -O-MTase methylates the ribose 2 0 -O position of the first and second nucleotide of viral mRNA, which sequesters it from the host immune system. The selected drug target proteins were screened against an in-house library of 123 antiviral drugs. Two promising drug molecules were identified for each protein based on their estimated free energy of binding (DG), the orientation of drug molecules in the active site and the interacting residues. The selected protein-drug complexes were then subjected to MD simulation, which consists of various structural parameters to equivalently reflect their physiological state. From the virtual screening results, two drug molecules were selected for each drug target protein [Paritaprevir (DG ¼ À9.8 kcal/mol) & Raltegravir (DG ¼ À7.8 kcal/mol) for 3CLpro and Dolutegravir (DG ¼ À9.4 kcal/mol) and Bictegravir (DG ¼ À8.4 kcal/mol) for 2 0 -OMTase]. After the extensive computational analysis, we proposed that Raltegravir, Paritaprevir, Bictegravir and Dolutegravir are excellent lead candidates for these crucial proteins and they could become potential therapeutic drugs against SARS-CoV-2.Abbreviations: 3CLpro: 3C-like proteinase; 2 0 -O-MTase: 2 0 -O-ribose methyltransferase; SARS-CoV-2: ARTICLE HISTORY

Andrographolide as a potential inhibitor of SARS-CoV-2 main protease: an in silico approach

“…guidetopharmacology.org/coronavirus.jsp) are in the process of being found in order to decrease the prognosis of the disease and life cycle of the virus. In silico studies of chemically synthetic drugs such as Paritaprevir and Raltegravir, Doultegravir and Bictegravir for the targets 3CLpro and 2 0 -OMTase (Khan, Jha, et al, 2020), theophylline and pyrimidone derivatives as possible inhibitors of RNA bound N terminal domain (Sarma et al, 2020) and Remdesivir, Saquinavir and Darunavir also with two natural compounds, flavone and coumarine derivatives for the inhibition of 3CL pro (Khan, Zia, et al, 2020) have been published. Though there are many targets are found for the treatment of COVID-19, the main protease (M pro ) of SARS-CoV-2 was chosen due to interest of treating infected patients, to stop the multiplication of virus within the cells, through which M pro was involved in the release of polypeptides which are functional extensive proteolysis and cleavage of the enzyme itself from the sites of genome, pp1a and ppa1ab .…”

Discovery of potential multi-target-directed ligands by targeting host-specific SARS-CoV-2 structurally conserved main protease

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SARS-CoV-2 RNA dependent RNA polymerase (RdRp) targeting: an in silico perspective

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