Identification of potential inhibitors against SARS-CoV-2 by targeting proteins responsible for envelope formation and virion assembly using docking based virtual screening, and pharmacokinetics approaches

Bhowmik, Deep; Nandi, Rajat; Jagadeesan, Rahul; Kumar, Niranjan; Prakash, Amresh; Kumar, Diwakar

doi:10.1016/j.meegid.2020.104451

Cited by 101 publications

(99 citation statements)

References 106 publications

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“…Recent studies have highlighted the potential of targeting SARS-CoV-2 E protein as a therapeutic strategy. Compounds like Rutin, Doxycycline [ 57 ], Nimbolin A [ 58 ], Belachinal, Macaflavanone E, Vibsanol B (Gupta M.K. et.…”

Section: Discussionmentioning

confidence: 99%

In silico identification of Tretinoin as a SARS-CoV-2 envelope (E) protein ion channel inhibitor

Dey

Borkotoky

Banerjee

2020

Computers in Biology and Medicine

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Viroporins are oligomeric, pore forming, viral proteins that play critical roles in the life cycle of pathogenic viruses. Viroporins like HIV-1 Vpu, Alphavirus 6K, Influenza M2, HCV p7, and Picornavirus 2B, form discrete aqueous passageways which mediate ion and small molecule transport in infected cells. The alterations in host membrane structures induced by viroporins is essential for key steps in the virus life cycle like entry, replication and egress. Any disruption in viroporin functionality severely compromises viral pathogenesis. The envelope (E) protein encoded by coronaviruses is a viroporin with ion channel activity and has been shown to be crucial for the assembly and pathophysiology of coronaviruses. We used a combination of virtual database screening, molecular docking, all-atom molecular dynamics simulation and MM-PBSA analysis to test four FDA approved drugs - Tretinoin, Mefenamic Acid, Ondansetron and Artemether - as potential inhibitors of ion channels formed by SARS-CoV-2 E protein. Interaction and binding energy analysis showed that electrostatic interactions and polar solvation energy were the major driving forces for binding of the drugs, with Tretinoin being the most promising inhibitor. Tretinoin bound within the the lumen of the channel formed by E protein, which is lined by hydrophobic residues like Phe, Val and Ala, indicating its potential for blocking the channel and inhibiting the viroporin functionality of E. In control simulations, tretinoin demonstrated a lower binding energy with a known target as compared to SARS-CoV-2 E protein. This work thus highlights the possibility of exploring Tretinoin as a potential SARS-CoV-2 E protein ion channel blocker and virus assembly inhibitor, which could be an important therapeutic strategy in the treatment for coronaviruses.

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Section: Discussionmentioning

confidence: 99%

In silico identification of Tretinoin as a SARS-CoV-2 envelope (E) protein ion channel inhibitor

Dey

Borkotoky

Banerjee

2020

Computers in Biology and Medicine

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“…It should be noted that simeprevir was also described to impact cellular innate immune responses 61 and Spike, were suggested for paritaprevir, grazoprevir and simeprevir by modelling studies. 53,67,[78][79][80][81][82] Future detailed molecular studies are required to fully define the viral targets of different HCV preprint (which was not certified by peer review) is the author/funder. All rights reserved.…”

Section: Discussionmentioning

confidence: 99%

Hepatitis C Virus Protease Inhibitors Show Differential Efficacy and Interactions with Remdesivir for Treatment of SARS-CoV-2in Vitro

Gammeltoft

Zhou

Galli

et al. 2020

Preprint

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Antivirals targeting SARS-CoV-2 could improve treatment of COVID-19. We evaluated the efficacy of clinically relevant hepatitis C virus (HCV) NS3 protease inhibitors (PI) against SARS-CoV-2 and their interactions with remdesivir, the only antiviral approved for treatment of COVID-19. HCV PI showed differential potency in VeroE6 cell-based antiviral assays based on detection of the SARS-CoV-2 Spike protein. Linear PI boceprevir, telaprevir and narlaprevir had 50% effective concentrations (EC50) of ≈40 μM. Among macrocyclic PI simeprevir, paritaprevir, grazoprevir, glecaprevir, voxilaprevir, vaniprevir, danoprevir and deldeprevir, simeprevir had the highest (EC50 15 μM) and glecaprevir the lowest (EC50 >178 μM) potency. Acyclic PI asunaprevir and faldaprevir had EC50 of 72 and 23 μM, respectively. ACH-806, an HCV NS3 protease co-factor NS4A inhibitor, had EC50 of 46 μM. For selected PI, potency was similar in human hepatoma Huh7.5 cells. Selectivity indexes, based on antiviral and cell viability assays, were highest for linear PI. In combination with remdesivir, linear PI boceprevir and narlaprevir showed antagonism, while macrocyclic PI simeprevir, paritaprevir and grazoprevir showed synergism with drug reduction indexes of up to 27 for simeprevir. Treatment of infected cultures with equipotent concentrations (1-fold EC50) of HCV PI revealed minor differences in barrier to SARS-CoV-2 escape. Complete viral suppression was achieved treating with ≥3-fold EC50 boceprevir or combination of 1-fold EC50 simeprevir with 0.4-fold EC50 remdesivir, not leading to significant viral suppression in single treatments. Considering potency, human plasma concentrations and synergism with remdesivir, simeprevir seemed the most promising compound for optimization of future antiviral treatments of COVID-19.

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“…This has now also become especially important because of its antiviral activity, including its reported activity against the Sars-CoV-2 virus [46,47]. Buckwheat is a promising source of rutin, the inhibitor of main protease and other protein targets of Sars-CoV-2 virus [48][49][50].…”

Section: Rutin Rutinosidase and Quercetinmentioning

confidence: 99%

Breeding Buckwheat for Increased Levels of Rutin, Quercetin and Other Bioactive Compounds with Potential Antiviral Effects

Luthar

Germ

Likar

et al. 2020

Plants

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Common buckwheat (Fagopyrum esculentum Moench) and Tartary buckwheat (Fagopyrum tataricum (L.) Gaertn.) are sources of many bioactive compounds, such as rutin, quercetin, emodin, fagopyrin and other (poly)phenolics. In damaged or milled grain under wet conditions, most of the rutin in common and Tartary buckwheat is degraded to quercetin by rutin-degrading enzymes (e.g., rutinosidase). From Tartary buckwheat varieties with low rutinosidase activity it is possible to prepare foods with high levels of rutin, with the preserved initial levels in the grain. The quercetin from rutin degradation in Tartary buckwheat grain is responsible in part for inhibition of α-glucosidase in the intestine, which helps to maintain normal glucose levels in the blood. Rutin and emodin have the potential for antiviral effects. Grain embryos are rich in rutin, so breeding buckwheat with the aim of producing larger embryos may be a promising strategy to increase the levels of rutin in common and Tartary buckwheat grain, and hence to improve its nutritional value.

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Identification of potential inhibitors against SARS-CoV-2 by targeting proteins responsible for envelope formation and virion assembly using docking based virtual screening, and pharmacokinetics approaches

Cited by 101 publications

References 106 publications

In silico identification of Tretinoin as a SARS-CoV-2 envelope (E) protein ion channel inhibitor

In silico identification of Tretinoin as a SARS-CoV-2 envelope (E) protein ion channel inhibitor

Hepatitis C Virus Protease Inhibitors Show Differential Efficacy and Interactions with Remdesivir for Treatment of SARS-CoV-2in Vitro

Breeding Buckwheat for Increased Levels of Rutin, Quercetin and Other Bioactive Compounds with Potential Antiviral Effects

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