Revisiting activity of some glucocorticoids as a potential inhibitor of SARS-CoV-2 main protease: theoretical study

Elmaaty, Ayman Abo; Alnajjar, Radwan; Hamed, Mohammed I. A.; Khattab, Muhammad; Khalifa, Mohamed M.; Al‐Karmalawy, Ahmed A.

doi:10.1039/d0ra10674g

Cited by 59 publications

(48 citation statements)

References 34 publications

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“…To this point, more studies are required to promote other FDA-approved drugs as new anti-SARS-CoV-2 drugs, especially in the case of drug-resistant variants. 30 , 31 In this study, we aimed to investigate the drug repurposing of 16 FDA-approved HCV DAA (listed in Figure 1 ) against SARS-CoV-2 via indirect targeting of hACE2 and CTSL, and direct targeting of S and M pro . This was achieved using in silico approaches and validated with an in vitro experiment for the most promising drug candidates.…”

Section: Introductionmentioning

confidence: 99%

Telaprevir is a potential drug for repurposing against SARS-CoV-2: computational and in vitro studies

Mahmoud

Mostafa

Al‐Karmalawy

et al. 2021

Heliyon

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Drug repurposing is an important approach to the assignment of already approved drugs for new indications. This technique bypasses some steps in the traditional drug approval system, which saves time and lives in the case of pandemics. Direct acting antivirals (DAAs) have repeatedly repurposed from treating one virus to another. In this study, 16 FDA-approved hepatitis C virus (HCV) DAA drugs were studied to explore their activities against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) human and viral targets. Among the 16 HCV DAA drugs, telaprevir has shown the best in silico evidence to work on both indirect human targets (cathepsin L [CTSL] and human angiotensin-converting enzyme 2 [ h ACE2] receptor) and direct viral targets (main protease [M pro ]). Moreover, the docked poses of telaprevir inside both h ACE2 and M pro were subjected to additional molecular dynamics simulations monitored by calculating the binding free energy using MM-GBSA. In vitro analysis of telaprevir showed inhibition of SARS-CoV-2 replication in cell culture (IC 50 = 11.552 μM, CC 50 = 60.865 μM, and selectivity index = 5.27). Accordingly, based on the in silico studies and supported by the presented in vitro analysis, we suggest that telaprevir may be considered for therapeutic development against SARS-CoV-2.

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Section: Introductionmentioning

confidence: 99%

Telaprevir is a potential drug for repurposing against SARS-CoV-2: computational and in vitro studies

Mahmoud

Mostafa

Al‐Karmalawy

et al. 2021

Heliyon

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“…Based on the aforementioned information concerning the essential role of Mpro in SARS-CoV-2 replication, besides the reported antiviral activity of P. dioica (L.) Merr [ 10 ], herein, and as an extension to our previous promising research targeting SARS-CoV-2 [ 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 ], we decided to examine the Mpro inhibitory activities of the four isolated compounds (ferulic acid 1 , rutin 2 , gallic acid 3 , and chlorogenic acid 4 ) -depicted in Figure 1 —using molecular docking and dynamics simulations. Moreover, to confirm our findings, we evaluated the anti-SARS-CoV-2 activities of the isolates ( 1 – 4 ) using MTT cytotoxic and inhibitory concentration 50 (IC 50 ) determination assays and examined their anti-inflammatory effects on different cytokines and genetic markers as well.…”

Section: Introductionmentioning

confidence: 99%

Pimenta dioica (L.) Merr. Bioactive Constituents Exert Anti-SARS-CoV-2 and Anti-Inflammatory Activities: Molecular Docking and Dynamics, In Vitro, and In Vivo Studies

et al. 2021

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In response to the urgent need to control Coronavirus disease 19 (COVID-19), this study aims to explore potential anti-SARS-CoV-2 agents from natural sources. Moreover, cytokine immunological responses to the viral infection could lead to acute respiratory distress which is considered a critical and life-threatening complication associated with the infection. Therefore, the anti-viral and anti-inflammatory agents can be key to the management of patients with COVID-19. Four bioactive compounds, namely ferulic acid 1, rutin 2, gallic acid 3, and chlorogenic acid 4 were isolated from the leaves of Pimenta dioica (L.) Merr (ethyl acetate extract) and identified using spectroscopic evidence. Furthermore, molecular docking and dynamics simulations were performed for the isolated and identified compounds (1–4) against SARS-CoV-2 main protease (Mpro) as a proposed mechanism of action. Furthermore, all compounds were tested for their half-maximal cytotoxicity (CC50) and SARS-CoV-2 inhibitory concentrations (IC50). Additionally, lung toxicity was induced in rats by mercuric chloride and the effects of treatment with P. dioca aqueous extract, ferulic acid 1, rutin 2, gallic acid 3, and chlorogenic acid 4 were recorded through measuring TNF-α, IL-1β, IL-2, IL-10, G-CSF, and genetic expression of miRNA 21-3P and miRNA-155 levels to assess their anti-inflammatory effects essential for COVID-19 patients. Interestingly, rutin 2, gallic acid 3, and chlorogenic acid 4 showed remarkable anti-SARS-CoV-2 activities with IC50 values of 31 µg/mL, 108 μg/mL, and 360 µg/mL, respectively. Moreover, the anti-inflammatory effects were found to be better in ferulic acid 1 and rutin 2 treatments. Our results could be promising for more advanced preclinical and clinical studies especially on rutin 2 either alone or in combination with other isolates for COVID-19 management.

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“…Therefore, in continuation of our previous work targeting SARS-CoV-2 main protease [ 6 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 ] as a promising anti-SARS-CoV-2 drug target, and taking into consideration the crucial role of M pro enzyme for SARS-CoV-2 replication (the main protease enzyme of SARS-CoV-2 and also known as 3C-like protease (3CL pro ), which is responsible for the cleavage of the coronavirus polyprotein at 11 specific sites), besides the previously mentioned activity of some NSAIDs towards different viruses, our perspective in this article is targeting the M pro enzyme through virtual screening of a small library of a subset of the approved NSAIDs ( Figure 2 ) via molecular docking of the ligands on the 3D crystal structure of M pro (PDB ID: 6LU7) [ 26 ]. Thus, we can investigate the best ligands that might have antiviral activity against SARS-CoV-2 or at least recommend the best NSAID members and prioritize them to be used in the treatment of the inflammatory cytokine storms accompanying some COVID-19 cases.…”

Section: Introductionmentioning

confidence: 54%

Computational Insights on the Potential of Some NSAIDs for Treating COVID-19: Priority Set and Lead Optimization

et al. 2021

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The discovery of drugs capable of inhibiting SARS-CoV-2 is a priority for human beings due to the severity of the global health pandemic caused by COVID-19. To this end, repurposing of FDA-approved drugs such as NSAIDs against COVID-19 can provide therapeutic alternatives that could be utilized as an effective safe treatment for COVID-19. The anti-inflammatory activity of NSAIDs is also advantageous in the treatment of COVID-19, as it was found that SARS-CoV-2 is responsible for provoking inflammatory cytokine storms resulting in lung damage. In this study, 40 FDA-approved NSAIDs were evaluated through molecular docking against the main protease of SARS-CoV-2. Among the tested compounds, sulfinpyrazone 2, indomethacin 3, and auranofin 4 were proposed as potential antagonists of COVID-19 main protease. Molecular dynamics simulations were also carried out for the most promising members of the screened NSAID candidates (2, 3, and 4) to unravel the dynamic properties of NSAIDs at the target receptor. The conducted quantum mechanical study revealed that the hybrid functional B3PW91 provides a good description of the spatial parameters of auranofin 4. Interestingly, a promising structure–activity relationship (SAR) was concluded from our study that could help in the future design of potential SARS-CoV-2 main protease inhibitors with expected anti-inflammatory effects as well. NSAIDs may be used by medicinal chemists as lead compounds for the development of potent SARS-CoV-2 (Mpro) inhibitors. In addition, some NSAIDs can be selectively designated for treatment of inflammation resulting from COVID-19.

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Revisiting activity of some glucocorticoids as a potential inhibitor of SARS-CoV-2 main protease: theoretical study

Abstract: The global breakout of COVID-19 and raised death toll has prompted scientists to develop novel drugs capable of inhibiting SARS-CoV-2.

Cited by 59 publications

References 34 publications

Telaprevir is a potential drug for repurposing against SARS-CoV-2: computational and in vitro studies

Telaprevir is a potential drug for repurposing against SARS-CoV-2: computational and in vitro studies

Pimenta dioica (L.) Merr. Bioactive Constituents Exert Anti-SARS-CoV-2 and Anti-Inflammatory Activities: Molecular Docking and Dynamics, In Vitro, and In Vivo Studies

Computational Insights on the Potential of Some NSAIDs for Treating COVID-19: Priority Set and Lead Optimization

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