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Exploring the pharmacological aspects of natural phytochemicals against SARS-CoV-2 Nsp14 through an in silico approach
The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), possesses an important bifunctional nonstructural protein (nsp14) with a C-terminal N7-methyltransferase (N7-MTase) domain and an N-terminal domain with exoribonuclease (ExoN) activity that is required for maintaining high-fidelity vi...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Springer Berlin Heidelberg
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10141836/ https://www.ncbi.nlm.nih.gov/pubmed/37131867 http://dx.doi.org/10.1007/s40203-023-00143-7 |
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author | De, Arkajit Bhattacharya, Somdatta Debroy, Bishal Bhattacharya, Arijit Pal, Kuntal |
author_facet | De, Arkajit Bhattacharya, Somdatta Debroy, Bishal Bhattacharya, Arijit Pal, Kuntal |
author_sort | De, Arkajit |
collection | PubMed |
description | The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), possesses an important bifunctional nonstructural protein (nsp14) with a C-terminal N7-methyltransferase (N7-MTase) domain and an N-terminal domain with exoribonuclease (ExoN) activity that is required for maintaining high-fidelity viral replication. Viruses use the error-prone replication mechanism, which results in high mutation rates, to adapt quickly to stressful situations. The efficiency with which nsp14 removes mismatched nucleotides due to the presence of ExoN activity protects viruses from mutagenesis. We investigated the pharmacological role of the phytochemicals (Baicalein, Bavachinin, Emodin, Kazinol F, Lycorine, Sinigrin, Procyanidin A2, Tanshinone IIA, Tanshinone IIB, Tomentin A, and Tomentin E) against the highly conserved nsp14 protein using docking-based computational analyses in search of new potential natural drug targets. The selected eleven phytochemicals failed to bind the active site of N7-Mtase in the global docking study, while the local docking study identified the top five phytochemicals with high binding energy scores ranging from − 9.0 to − 6.4 kcal/mol. Procyanidin A2 and Tomentin A showed the highest docking score of − 9.0 and − 8.1 kcal/mol, respectively. Local docking of isoform variants was also conducted, yielding the top five phytochemicals, with Procyanidin A1 having the highest binding energy value of − 9.1 kcal/mol. The phytochemicals were later tested for pharmacokinetics and pharmacodynamics analysis for Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) which resulted in choosing Tomentin A as a potential candidate. The molecular dynamics simulations studies of nsp14 revealed significant conformational changes upon complex formation with the identified compound, implying that these phytochemicals could be used as safe nutraceuticals which will impart long-term immunological competence in the human population against CoVs. GRAPHICAL ABSTRACT: [Image: see text] SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s40203-023-00143-7. |
format | Online Article Text |
id | pubmed-10141836 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Springer Berlin Heidelberg |
record_format | MEDLINE/PubMed |
spelling | pubmed-101418362023-05-01 Exploring the pharmacological aspects of natural phytochemicals against SARS-CoV-2 Nsp14 through an in silico approach De, Arkajit Bhattacharya, Somdatta Debroy, Bishal Bhattacharya, Arijit Pal, Kuntal In Silico Pharmacol Original Research The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), possesses an important bifunctional nonstructural protein (nsp14) with a C-terminal N7-methyltransferase (N7-MTase) domain and an N-terminal domain with exoribonuclease (ExoN) activity that is required for maintaining high-fidelity viral replication. Viruses use the error-prone replication mechanism, which results in high mutation rates, to adapt quickly to stressful situations. The efficiency with which nsp14 removes mismatched nucleotides due to the presence of ExoN activity protects viruses from mutagenesis. We investigated the pharmacological role of the phytochemicals (Baicalein, Bavachinin, Emodin, Kazinol F, Lycorine, Sinigrin, Procyanidin A2, Tanshinone IIA, Tanshinone IIB, Tomentin A, and Tomentin E) against the highly conserved nsp14 protein using docking-based computational analyses in search of new potential natural drug targets. The selected eleven phytochemicals failed to bind the active site of N7-Mtase in the global docking study, while the local docking study identified the top five phytochemicals with high binding energy scores ranging from − 9.0 to − 6.4 kcal/mol. Procyanidin A2 and Tomentin A showed the highest docking score of − 9.0 and − 8.1 kcal/mol, respectively. Local docking of isoform variants was also conducted, yielding the top five phytochemicals, with Procyanidin A1 having the highest binding energy value of − 9.1 kcal/mol. The phytochemicals were later tested for pharmacokinetics and pharmacodynamics analysis for Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) which resulted in choosing Tomentin A as a potential candidate. The molecular dynamics simulations studies of nsp14 revealed significant conformational changes upon complex formation with the identified compound, implying that these phytochemicals could be used as safe nutraceuticals which will impart long-term immunological competence in the human population against CoVs. GRAPHICAL ABSTRACT: [Image: see text] SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s40203-023-00143-7. Springer Berlin Heidelberg 2023-04-28 /pmc/articles/PMC10141836/ /pubmed/37131867 http://dx.doi.org/10.1007/s40203-023-00143-7 Text en © The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature 2023, Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law. |
spellingShingle | Original Research De, Arkajit Bhattacharya, Somdatta Debroy, Bishal Bhattacharya, Arijit Pal, Kuntal Exploring the pharmacological aspects of natural phytochemicals against SARS-CoV-2 Nsp14 through an in silico approach |
title | Exploring the pharmacological aspects of natural phytochemicals against SARS-CoV-2 Nsp14 through an in silico approach |
title_full | Exploring the pharmacological aspects of natural phytochemicals against SARS-CoV-2 Nsp14 through an in silico approach |
title_fullStr | Exploring the pharmacological aspects of natural phytochemicals against SARS-CoV-2 Nsp14 through an in silico approach |
title_full_unstemmed | Exploring the pharmacological aspects of natural phytochemicals against SARS-CoV-2 Nsp14 through an in silico approach |
title_short | Exploring the pharmacological aspects of natural phytochemicals against SARS-CoV-2 Nsp14 through an in silico approach |
title_sort | exploring the pharmacological aspects of natural phytochemicals against sars-cov-2 nsp14 through an in silico approach |
topic | Original Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10141836/ https://www.ncbi.nlm.nih.gov/pubmed/37131867 http://dx.doi.org/10.1007/s40203-023-00143-7 |
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