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Effect of drug metabolism in the treatment of SARS-CoV-2 from an entirely computational perspective

Understanding the effects of metabolism on the rational design of novel and more effective drugs is still a considerable challenge. To the best of our knowledge, there are no entirely computational strategies that make it possible to predict these effects. From this perspective, the development of s...

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Autores principales: de Jesus, João Paulo Almirão, Assis, Letícia Cristina, de Castro, Alexandre Alves, da Cunha, Elaine Fontes Ferreira, Nepovimova, Eugenie, Kuca, Kamil, de Castro Ramalho, Teodorico, de Almeida La Porta, Felipe
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8497625/
https://www.ncbi.nlm.nih.gov/pubmed/34620963
http://dx.doi.org/10.1038/s41598-021-99451-1
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author de Jesus, João Paulo Almirão
Assis, Letícia Cristina
de Castro, Alexandre Alves
da Cunha, Elaine Fontes Ferreira
Nepovimova, Eugenie
Kuca, Kamil
de Castro Ramalho, Teodorico
de Almeida La Porta, Felipe
author_facet de Jesus, João Paulo Almirão
Assis, Letícia Cristina
de Castro, Alexandre Alves
da Cunha, Elaine Fontes Ferreira
Nepovimova, Eugenie
Kuca, Kamil
de Castro Ramalho, Teodorico
de Almeida La Porta, Felipe
author_sort de Jesus, João Paulo Almirão
collection PubMed
description Understanding the effects of metabolism on the rational design of novel and more effective drugs is still a considerable challenge. To the best of our knowledge, there are no entirely computational strategies that make it possible to predict these effects. From this perspective, the development of such methodologies could contribute to significantly reduce the side effects of medicines, leading to the emergence of more effective and safer drugs. Thereby, in this study, our strategy is based on simulating the electron ionization mass spectrometry (EI-MS) fragmentation of the drug molecules and combined with molecular docking and ADMET models in two different situations. In the first model, the drug is docked without considering the possible metabolic effects. In the second model, each of the intermediates from the EI-MS results is docked, and metabolism occurs before the drug accesses the biological target. As a proof of concept, in this work, we investigate the main antiviral drugs used in clinical research to treat COVID-19. As a result, our strategy made it possible to assess the biological activity and toxicity of all potential by-products. We believed that our findings provide new chemical insights that can benefit the rational development of novel drugs in the future.
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spelling pubmed-84976252021-10-12 Effect of drug metabolism in the treatment of SARS-CoV-2 from an entirely computational perspective de Jesus, João Paulo Almirão Assis, Letícia Cristina de Castro, Alexandre Alves da Cunha, Elaine Fontes Ferreira Nepovimova, Eugenie Kuca, Kamil de Castro Ramalho, Teodorico de Almeida La Porta, Felipe Sci Rep Article Understanding the effects of metabolism on the rational design of novel and more effective drugs is still a considerable challenge. To the best of our knowledge, there are no entirely computational strategies that make it possible to predict these effects. From this perspective, the development of such methodologies could contribute to significantly reduce the side effects of medicines, leading to the emergence of more effective and safer drugs. Thereby, in this study, our strategy is based on simulating the electron ionization mass spectrometry (EI-MS) fragmentation of the drug molecules and combined with molecular docking and ADMET models in two different situations. In the first model, the drug is docked without considering the possible metabolic effects. In the second model, each of the intermediates from the EI-MS results is docked, and metabolism occurs before the drug accesses the biological target. As a proof of concept, in this work, we investigate the main antiviral drugs used in clinical research to treat COVID-19. As a result, our strategy made it possible to assess the biological activity and toxicity of all potential by-products. We believed that our findings provide new chemical insights that can benefit the rational development of novel drugs in the future. Nature Publishing Group UK 2021-10-07 /pmc/articles/PMC8497625/ /pubmed/34620963 http://dx.doi.org/10.1038/s41598-021-99451-1 Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open Access This 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 Article
de Jesus, João Paulo Almirão
Assis, Letícia Cristina
de Castro, Alexandre Alves
da Cunha, Elaine Fontes Ferreira
Nepovimova, Eugenie
Kuca, Kamil
de Castro Ramalho, Teodorico
de Almeida La Porta, Felipe
Effect of drug metabolism in the treatment of SARS-CoV-2 from an entirely computational perspective
title Effect of drug metabolism in the treatment of SARS-CoV-2 from an entirely computational perspective
title_full Effect of drug metabolism in the treatment of SARS-CoV-2 from an entirely computational perspective
title_fullStr Effect of drug metabolism in the treatment of SARS-CoV-2 from an entirely computational perspective
title_full_unstemmed Effect of drug metabolism in the treatment of SARS-CoV-2 from an entirely computational perspective
title_short Effect of drug metabolism in the treatment of SARS-CoV-2 from an entirely computational perspective
title_sort effect of drug metabolism in the treatment of sars-cov-2 from an entirely computational perspective
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8497625/
https://www.ncbi.nlm.nih.gov/pubmed/34620963
http://dx.doi.org/10.1038/s41598-021-99451-1
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