Screening of drug databank against WT and mutant main protease of SARS-CoV-2: Towards finding potential compound for repurposing against COVID-19

Abstract

Although several pharmacological agents are under investigation to be repurposed as therapeutic against COVID-19, not much success has been achieved yet. So, the search for an effective and active option for the treatment of COVID-19 is still a big challenge. The Spike protein (S), RNA-dependent RNA polymerase (RdRp), and Main protease (Mpro) are considered to be the primary therapeutic drug target for COVID-19. In this study we have screened the drugbank compound library against the Main Protease. But our search was not limited to just Mpro. Like other viruses, SARS-CoV-2, have also acquired unique mutations. These mutations within the active site of these target proteins may be an important factor hindering effective drug candidate development. In the present study we identified important active site mutations within the SARS-CoV-2 Mpro (Y54C, N142S, T190I and A191V). Further the drugbank database was computationally screened against Mpro and the selected mutants. Finally, we came up with the common molecules effective against the wild type (WT) and all the selected Mpro. The study found Imiglitazar, was found to be the most active compound against the wild type of Mpro. While PF-03715455 (Y54C), Salvianolic acid A (N142S and T190I), and Montelukast (A191V) were found to be most active against the other selected mutants. It was also found that some other compounds such as Acteoside, 4-Amino-N- {4-[2-(2,6-Dimethyl-Phenoxy)-Acetylamino]-3-Hydroxy-1-Isobutyl-5-Phenyl-Pentyl}-Benzamide, PF-00610355, 4-Amino-N-4-[2-(2,6-Dimethyl-Phenoxy)-Acetylamino]-3-Hydroxy-1-Isobutyl-5-Phenyl-Pentyl}-Benzamide and Atorvastatin were showing high efficacy against the WT as well as other selected mutants. We believe that these molecules will provide a better and effective option for the treatment of COVID-19 clinical manifestations.

Montelukast and Coronavirus Disease 2019: A Scoping Review

“…Our search included 11 (30.5%) in silico studies. A total of 8 out of 11 (72.7%) considered MK as a potential main protease (Mpro) inhibitor of SARS-CoV-2 21,23,[36][37][38][39][40][41] and two (18.2%) expressed MK's ability to dock the RNA dependent RNA polymerase (RdRp) site of SARS-CoV-2. 21,42 Spike glycoprotein site (S1 subunit) 23 and papain-like protease (PLpro) 22 were the other connection sites, each reported in one study.…”

“…One of the articles introduced MK as an effective drug on mutated SARS-CoV-2, mostly against A191V site mutation within the SARS-CoV-2 Mpro. 41 Six articles (16.7%) proposed MK as a potential treatment in SARS-CoV-2 positive patients through altering NF-kB signaling pathway, targeting the increased vascular permeability, suppressing recruitment of the innate immune response as well as bronchoconstriction resulted from cytokine release and also lung injury. 14,15,[29][30][31]43 MK was evaluated as the only applied medicine in four out of six surveys.…”

Synergistic Interactions of Repurposed Drugs that Inhibit Nsp1, a Major Virulence Factor for COVID-19

“…In addition, Montelukast, Ponatinib, and Rilpivirine have been suggested as treatments for COVID-19 in other studies. In silico docking studies suggest that Montelukast binds to the SARS-CoV-2 proteins Mpro [53], RdRp [53], and 3CL [54]. In Vero6 cells, Montelukast inhibited SARS-CoV-2 replication, albeit at a high IC50 of 18.82 µM [55].…”

Drug targeting Nsp1-ribosomal complex shows antiviral activity against SARS-CoV-2

“…Montelukast is a leukotriene receptor antagonist and repurposing montelukast for tackling cytokine storms in COVID-19 patients has been suggested (Sanghai and Tranmer, 2020) and hospitalized COVID-19 patients that were given montelukast had significantly fewer events of clinical deterioration (Khan et al, 2021). Montelukast also appears as a hit against the SARS-CoV-2 main protease, (M pro ) protease, in computational studies (Abu-Saleh et al, 2020; Sharma et al, 2021). However, Chunlong et al .…”