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Computational approach towards the design of artemisinin–thymoquinone hybrids against main protease of SARS-COV-2
BACKGROUND: The sanitary emergency installed in the world, generated by the pandemic of COVID-19, instigates the search for scientific strategies to mitigate the damage caused by the disease to different sectors of society. The disease caused by the coronavirus, SARS-CoV-2, reached 216 countries/ter...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Springer Berlin Heidelberg
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8419828/ https://www.ncbi.nlm.nih.gov/pubmed/34514004 http://dx.doi.org/10.1186/s43094-021-00334-z |
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author | de Oliveira, Victor Moreira da Rocha, Matheus Nunes Magalhães, Emanuel Paula da Silva Mendes, Francisco Rogênio Marinho, Márcia Machado de Menezes, Ramon Róseo Paula Pessoa Bezerra Sampaio, Tiago Lima dos Santos, Hélcio Silva Martins, Alice Maria Costa Marinho, Emmanuel Silva |
author_facet | de Oliveira, Victor Moreira da Rocha, Matheus Nunes Magalhães, Emanuel Paula da Silva Mendes, Francisco Rogênio Marinho, Márcia Machado de Menezes, Ramon Róseo Paula Pessoa Bezerra Sampaio, Tiago Lima dos Santos, Hélcio Silva Martins, Alice Maria Costa Marinho, Emmanuel Silva |
author_sort | de Oliveira, Victor Moreira |
collection | PubMed |
description | BACKGROUND: The sanitary emergency installed in the world, generated by the pandemic of COVID-19, instigates the search for scientific strategies to mitigate the damage caused by the disease to different sectors of society. The disease caused by the coronavirus, SARS-CoV-2, reached 216 countries/territories, where about 199 million people were reported with the infection. Of these, more than 4 million died. In this sense, strategies involving the development of new antiviral molecules are extremely important. The main protease (Mpro) from SARS-CoV-2 is an important target, which has been widely studied for antiviral treatment. This work aims to perform a screening of pharmacodynamics and pharmacokinetics of synthetic hybrids from thymoquinone and artemisin (THY-ART) against COVID-19. RESULTS: Molecular docking studies indicated that hybrids of artemisinin and thymoquinone showed a relevant interaction with the active fraction of the enzyme Mpro, when compared to the reference drugs. Furthermore, hybrids show an improvement in the interaction of substances with the enzyme, mainly due to the higher frequency of interactions with the Thr199 residue. ADMET studies indicated that hybrids tend to permeate biological membranes, allowing good human intestinal absorption, with low partition to the central nervous system, potentiation for CYP-450 enzyme inhibitors, low risk of toxicity compared to commercially available drugs, considering mainly mutagenicity and cardiotoxicity, low capacity of hybrids to permeate the blood–brain barrier, high absorption and moderate permeability in Caco-2 cells. In addition, T1–T7 tend to have a better distribution of their available fractions to carry out diffusion and transport across cell membranes, as well as increase the energy of interaction with the SARS-CoV-2 target. CONCLUSIONS: Hybrid products of artemisinin and thymoquinone have the potential to inhibit Mpro, with desirable pharmacokinetic and toxicity characteristics compared to commercially available drugs, being indicated for preclinical and subsequent clinical studies against SARS-CoV-2. Emphasizing the possibility of synergistic use with currently used drugs in order to increase half-life and generate a possible synergistic effect. This work represents an important step for the development of specific drugs against COVID-19. |
format | Online Article Text |
id | pubmed-8419828 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Springer Berlin Heidelberg |
record_format | MEDLINE/PubMed |
spelling | pubmed-84198282021-09-07 Computational approach towards the design of artemisinin–thymoquinone hybrids against main protease of SARS-COV-2 de Oliveira, Victor Moreira da Rocha, Matheus Nunes Magalhães, Emanuel Paula da Silva Mendes, Francisco Rogênio Marinho, Márcia Machado de Menezes, Ramon Róseo Paula Pessoa Bezerra Sampaio, Tiago Lima dos Santos, Hélcio Silva Martins, Alice Maria Costa Marinho, Emmanuel Silva Futur J Pharm Sci Research BACKGROUND: The sanitary emergency installed in the world, generated by the pandemic of COVID-19, instigates the search for scientific strategies to mitigate the damage caused by the disease to different sectors of society. The disease caused by the coronavirus, SARS-CoV-2, reached 216 countries/territories, where about 199 million people were reported with the infection. Of these, more than 4 million died. In this sense, strategies involving the development of new antiviral molecules are extremely important. The main protease (Mpro) from SARS-CoV-2 is an important target, which has been widely studied for antiviral treatment. This work aims to perform a screening of pharmacodynamics and pharmacokinetics of synthetic hybrids from thymoquinone and artemisin (THY-ART) against COVID-19. RESULTS: Molecular docking studies indicated that hybrids of artemisinin and thymoquinone showed a relevant interaction with the active fraction of the enzyme Mpro, when compared to the reference drugs. Furthermore, hybrids show an improvement in the interaction of substances with the enzyme, mainly due to the higher frequency of interactions with the Thr199 residue. ADMET studies indicated that hybrids tend to permeate biological membranes, allowing good human intestinal absorption, with low partition to the central nervous system, potentiation for CYP-450 enzyme inhibitors, low risk of toxicity compared to commercially available drugs, considering mainly mutagenicity and cardiotoxicity, low capacity of hybrids to permeate the blood–brain barrier, high absorption and moderate permeability in Caco-2 cells. In addition, T1–T7 tend to have a better distribution of their available fractions to carry out diffusion and transport across cell membranes, as well as increase the energy of interaction with the SARS-CoV-2 target. CONCLUSIONS: Hybrid products of artemisinin and thymoquinone have the potential to inhibit Mpro, with desirable pharmacokinetic and toxicity characteristics compared to commercially available drugs, being indicated for preclinical and subsequent clinical studies against SARS-CoV-2. Emphasizing the possibility of synergistic use with currently used drugs in order to increase half-life and generate a possible synergistic effect. This work represents an important step for the development of specific drugs against COVID-19. Springer Berlin Heidelberg 2021-09-06 2021 /pmc/articles/PMC8419828/ /pubmed/34514004 http://dx.doi.org/10.1186/s43094-021-00334-z Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Research de Oliveira, Victor Moreira da Rocha, Matheus Nunes Magalhães, Emanuel Paula da Silva Mendes, Francisco Rogênio Marinho, Márcia Machado de Menezes, Ramon Róseo Paula Pessoa Bezerra Sampaio, Tiago Lima dos Santos, Hélcio Silva Martins, Alice Maria Costa Marinho, Emmanuel Silva Computational approach towards the design of artemisinin–thymoquinone hybrids against main protease of SARS-COV-2 |
title | Computational approach towards the design of artemisinin–thymoquinone hybrids against main protease of SARS-COV-2 |
title_full | Computational approach towards the design of artemisinin–thymoquinone hybrids against main protease of SARS-COV-2 |
title_fullStr | Computational approach towards the design of artemisinin–thymoquinone hybrids against main protease of SARS-COV-2 |
title_full_unstemmed | Computational approach towards the design of artemisinin–thymoquinone hybrids against main protease of SARS-COV-2 |
title_short | Computational approach towards the design of artemisinin–thymoquinone hybrids against main protease of SARS-COV-2 |
title_sort | computational approach towards the design of artemisinin–thymoquinone hybrids against main protease of sars-cov-2 |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8419828/ https://www.ncbi.nlm.nih.gov/pubmed/34514004 http://dx.doi.org/10.1186/s43094-021-00334-z |
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