Drug targets, mechanisms of drug action, and therapeutics against SARS-CoV-2

Jena, N. R.

doi:10.1016/j.chphi.2021.100011

Cited by 21 publications

(28 citation statements)

References 155 publications

(224 reference statements)

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“…On the other hand, SARS-CoV-2 replication requires the functional proteins nsp4 that is released through the cleavage of polyproteins pp1a and pp1ab [42]. This cleavage is mediated by M pro , and consequently, inhibiting M pro hinders the ability of the virus to replicate within host cells [43]. Targeting M pro can provide high selectivity as it has a preference for a glutamine substrate, which is missing in the host proteases [44].…”

Section: Discussionmentioning

confidence: 99%

Iterated Virtual Screening-Assisted Antiviral and Enzyme Inhibition Assays Reveal the Discovery of Novel Promising Anti-SARS-CoV-2 with Dual Activity

Hamdy

Fayed

Mostafa

et al. 2021

IJMS

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Unfortunately, COVID-19 is still a threat to humankind and has a dramatic impact on human health, social life, the world economy, and food security. With the limited number of suggested therapies under clinical trials, the discovery of novel therapeutic agents is essential. Here, a previously identified anti-SARS-CoV-2 compound named Compound 13 (1,2,5-Oxadiazole-3-carboximidic acid, 4,4’-(methylenediimino) bis,bis[[(2-hydroxyphenyl)methylene]hydrazide) was subjected to an iterated virtual screening against SARS-CoV-2 Mpro using a combination of Ligand Designer and PathFinder. PathFinder, a computational reaction enumeration tool, was used for the rapid generation of enumerated structures via default reaction library. Ligand designer was employed for the computerized lead optimization and selection of the best structural modification that resulted in a favorable ligand–protein complex. The obtained compounds that showed the best binding to Mpro were re-screened against TMPRSS2, leading to the identification of 20 shared compounds. The compounds were further visually inspected, which resulted in the identification of five shared compounds M1–5 with dual binding affinity. In vitro evaluation and enzyme inhibition assay indicated that M3, an analogue of Compound 13 afforded by replacing the phenolic moiety with pyridinyl, possesses an improved antiviral activity and safety. M3 displayed in vitro antiviral activity with IC50 0.016 µM and Mpro inhibition activity with IC50 0.013 µM, 7-fold more potent than the parent Compound 13 and potent than the antivirals drugs that are currently under clinical trials. Moreover, M3 showed potent activity against human TMPRSS2 and furin enzymes with IC50 0.05, and 0.08 µM, respectively. Molecular docking, WaterMap analysis, molecular dynamics simulation, and R-group analysis confirmed the superiority of the binding fit to M3 with the target enzymes. WaterMap analysis calculated the thermodynamic properties of the hydration site in the binding pocket that significantly affects the biological activity. Loading M3 on zinc oxide nanoparticles (ZnO NPs) increased the antiviral activity of the compound 1.5-fold, while maintaining a higher safety profile. In conclusion, lead optimized discovery following an iterated virtual screening in association with molecular docking and biological evaluation revealed a novel compound named M3 with promising dual activity against SARS-CoV-2. The compound deserves further investigation for potential clinical-based studies.

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Section: Discussionmentioning

confidence: 99%

Iterated Virtual Screening-Assisted Antiviral and Enzyme Inhibition Assays Reveal the Discovery of Novel Promising Anti-SARS-CoV-2 with Dual Activity

Hamdy

Fayed

Mostafa

et al. 2021

IJMS

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“…This would ultimately hinder the replication of the viral RNA. However, as it was presumed that RDV would be converted to the RMP before it can get inserted into the RNA strand (Jena, 2020a(Jena, , 2020cYin et al, 2020), it would be interesting to understand, the detailed conversion mechanism of RDV to RMP in the presence and absence of RdRp.…”

Section: Md-simulations Of Remdesivir (Rdv)mentioning

confidence: 99%

“…As RDV and dPdZ bind strongly to these channels, their inhibitory activity would be higher than that of RMP. However, as RDV gets converted to RMP (Jena, 2020a;2020c;Yin et al, 2020) as the final metabolite and its binding with RdRp is weaker compared to dPdZ, the latter would act as a strong inhibitor of RdRp.…”

Section: Simulations Of Dpdzmentioning

confidence: 99%

“…Recently, Remdesivir was shown to inhibit RdRp of SARS-CoV-2 and hence was approved for emergency use in the case of COVID-19 patients by the Food and Drug Administration (FDA) (Chaar & Makuch, 2020;Hendaus, 2020;Pruijssers et al, 2020). It was hypothesized that Remdesivir (RDV) (Figure 1a) gets converted first to Remdesivir monophosphate (RMP) (Figure 1b) and then to Remdesivir triphosphate (RTP) (Figure 1c) before binding to the protein (Jena, 2020a;Warren et al, 2016). However, as RTP does not immediately inhibit RdRp, but allows insertions of 2-4 new nucleotides before eventually halting the chain-elongation reaction (Gordon et al, 2020), it would likely make a covalent bond with the next nucleotide in RNA.…”

Section: Introductionmentioning

confidence: 99%

“…Further, recently it is proposed that RDV can induce basepair mutations in the viral RNA and for this it needs to be converted to RMP (Jena, 2020c). Hence, it is plausible that RTP gets converted back again to RMP in the presence of RdRp (Jena, 2020a(Jena, , 2020cYin et al, 2020). However, the detailed mechanisms of these conversions are not yet fully understood.…”

Section: Introductionmentioning

confidence: 99%

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Artificially expanded genetic information systems (AEGISs) as potent inhibitors of the RNA-dependent RNA polymerase of the SARS-CoV-2

Jena

Pant

Srivastava

2021

Journal of Biomolecular Structure and Dynamics

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The recent outbreak of the SARS-CoV-2 infection has affected the lives and economy of more than 200 countries. The unavailability of virus-specific drugs has created an opportunity to identify potential therapeutic agents that can control the rapid transmission of this pandemic. Here, the mechanisms of the inhibition of the RNA-dependent RNA polymerase (RdRp), responsible for the replication of the virus in host cells, are examined by different ligands, such as Remdesivir (RDV), Remdesivir monophosphate (RMP), and several artificially expanded genetic information systems (AEGISs) including their different sequences by employing molecular docking, MD simulations, and MM/GBSA techniques. It is found that the binding of RDV to RdRp may block the RNA binding site. However, RMP would acquire a partially flipped conformation and may allow the viral RNA to enter into the binding site. The internal dynamics of RNA and RdRp may help RMP to regain its original position, where it may inhibit the RNA-chain elongation reaction. Remarkably, AEGISs are found to obstruct the binding site of RNA. It is shown that dPdZ, a two-nucleotide sequence containing P and Z would bind to RdRp very strongly and may occupy the positions of two nucleotides in the RNA strand, thereby denying access of the substrate–binding site to the viral RNA. Thus, it is proposed that the AEGISs may act as novel therapeutic candidates against the SARS-CoV-2. However, in vivo evaluations of their potencies and toxicities are needed before using them against COVID-19.

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Repurposing of FDA‐approved drugs against active site and potential allosteric drug‐binding sites of COVID‐19 main protease

et al. 2021

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The novel coronavirus disease 2019 (COVID‐19) caused by severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) still has serious negative effects on health, social life, and economics. Recently, vaccines from various companies have been urgently approved to control SARS‐CoV‐2 infections. However, any specific antiviral drug has not been confirmed so far for regular treatment. An important target is the main protease (M pro ), which plays a major role in replication of the virus. In this study, Gaussian and residue network models are employed to reveal two distinct potential allosteric sites on M pro that can be evaluated as drug targets besides the active site. Then, Food and Drug Administration (FDA)‐approved drugs are docked to three distinct sites with flexible docking using AutoDock Vina to identify potential drug candidates. Fourteen best molecule hits for the active site of M pro are determined. Six of these also exhibit high docking scores for the potential allosteric regions. Full‐atom molecular dynamics simulations with MM‐GBSA method indicate that compounds docked to active and potential allosteric sites form stable interactions with high binding free energy (∆ G bind ) values. ∆ G bind values reach −52.06 kcal/mol for the active site, −51.08 kcal/mol for the potential allosteric site 1, and − 42.93 kcal/mol for the potential allosteric site 2. Energy decomposition calculations per residue elucidate key binding residues stabilizing the ligands that can further serve to design pharmacophores. This systematic and efficient computational analysis successfully determines ivermectine, diosmin, and selinexor currently subjected to clinical trials, and further proposes bromocriptine, elbasvir as M pro inhibitor candidates to be evaluated against SARS‐CoV‐2 infections.

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Drug targets, mechanisms of drug action, and therapeutics against SARS-CoV-2

Cited by 21 publications

References 155 publications

Iterated Virtual Screening-Assisted Antiviral and Enzyme Inhibition Assays Reveal the Discovery of Novel Promising Anti-SARS-CoV-2 with Dual Activity

Iterated Virtual Screening-Assisted Antiviral and Enzyme Inhibition Assays Reveal the Discovery of Novel Promising Anti-SARS-CoV-2 with Dual Activity

Artificially expanded genetic information systems (AEGISs) as potent inhibitors of the RNA-dependent RNA polymerase of the SARS-CoV-2

Repurposing of FDA‐approved drugs against active site and potential allosteric drug‐binding sites of COVID‐19 main protease

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