Mutations in Main Protease of SARS CoV-2 Decreased Boceprevir Affinity
Autor(a) principal: | |
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Data de Publicação: | 2021 |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | Brazilian Archives of Biology and Technology |
Texto Completo: | http://old.scielo.br/scielo.php?script=sci_arttext&pid=S1516-89132021000100434 |
Resumo: | Abstract The coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a global health emergency. The main protease (Mpro) is crucial for the life cycle of coronaviruses. Boceprevir is a potential inhibitor and drug candidate for the Mpro of SARS-CoV-2. In this study, changes in the protein structure of the Mpro due to mutations in SARS-CoV-2 and the effects of these changes on boceprevir affinity, an important potential therapeutic agent, were investigated. The mutations were analyzed with RDP4 and MegaX. A three-dimensional model of mutant Mpro was generated by ProMod3. Qualitative Model Energy Analysis, ProSA, and MolProbity tools were used for structural validation and modeling of the wild-type and mutant Mpro proteins. Topological differences of the wild-type and mutant Mpro were calculated with the i-Tasser TM-Score. Molecular docking was performed using AutoDock 4.2. Functional dynamic structure models were created with DynOmics. Seven mutations (L89F, K90R, P108S, A191V, T224A, A234V and S254F) were detected in the Mpro of SARS-CoV-2. The mutations caused a decrease in the affinity of boceprevir, a potential protease inhibitor. The boceprevir was docked to the active site of Mpro, and the binding energies were −10.34 and −9.41 kcal.mol-1 for the wild-type and the mutant, respectively. The Debye-Waller factors calculated by elastic network model analysis were 0.58 and 0.64 Å2 for the wild-type Mpro and mutant Mpro, respectively. Mutations in structures that are important drug targets for SARS-CoV-2 may render existing therapeutics ineffective in its treatment. |
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Mutations in Main Protease of SARS CoV-2 Decreased Boceprevir Affinityboceprevir affinitydrug validitymain proteasemutationSARS-CoV-2Abstract The coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a global health emergency. The main protease (Mpro) is crucial for the life cycle of coronaviruses. Boceprevir is a potential inhibitor and drug candidate for the Mpro of SARS-CoV-2. In this study, changes in the protein structure of the Mpro due to mutations in SARS-CoV-2 and the effects of these changes on boceprevir affinity, an important potential therapeutic agent, were investigated. The mutations were analyzed with RDP4 and MegaX. A three-dimensional model of mutant Mpro was generated by ProMod3. Qualitative Model Energy Analysis, ProSA, and MolProbity tools were used for structural validation and modeling of the wild-type and mutant Mpro proteins. Topological differences of the wild-type and mutant Mpro were calculated with the i-Tasser TM-Score. Molecular docking was performed using AutoDock 4.2. Functional dynamic structure models were created with DynOmics. Seven mutations (L89F, K90R, P108S, A191V, T224A, A234V and S254F) were detected in the Mpro of SARS-CoV-2. The mutations caused a decrease in the affinity of boceprevir, a potential protease inhibitor. The boceprevir was docked to the active site of Mpro, and the binding energies were −10.34 and −9.41 kcal.mol-1 for the wild-type and the mutant, respectively. The Debye-Waller factors calculated by elastic network model analysis were 0.58 and 0.64 Å2 for the wild-type Mpro and mutant Mpro, respectively. Mutations in structures that are important drug targets for SARS-CoV-2 may render existing therapeutics ineffective in its treatment.Instituto de Tecnologia do Paraná - Tecpar2021-01-01info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersiontext/htmlhttp://old.scielo.br/scielo.php?script=sci_arttext&pid=S1516-89132021000100434Brazilian Archives of Biology and Technology v.64 2021reponame:Brazilian Archives of Biology and Technologyinstname:Instituto de Tecnologia do Paraná (Tecpar)instacron:TECPAR10.1590/1678-4324-2021200803info:eu-repo/semantics/openAccessAkbulut,Ekremeng2022-02-18T00:00:00Zoai:scielo:S1516-89132021000100434Revistahttps://www.scielo.br/j/babt/https://old.scielo.br/oai/scielo-oai.phpbabt@tecpar.br||babt@tecpar.br1678-43241516-8913opendoar:2022-02-18T00:00Brazilian Archives of Biology and Technology - Instituto de Tecnologia do Paraná (Tecpar)false |
dc.title.none.fl_str_mv |
Mutations in Main Protease of SARS CoV-2 Decreased Boceprevir Affinity |
title |
Mutations in Main Protease of SARS CoV-2 Decreased Boceprevir Affinity |
spellingShingle |
Mutations in Main Protease of SARS CoV-2 Decreased Boceprevir Affinity Akbulut,Ekrem boceprevir affinity drug validity main protease mutation SARS-CoV-2 |
title_short |
Mutations in Main Protease of SARS CoV-2 Decreased Boceprevir Affinity |
title_full |
Mutations in Main Protease of SARS CoV-2 Decreased Boceprevir Affinity |
title_fullStr |
Mutations in Main Protease of SARS CoV-2 Decreased Boceprevir Affinity |
title_full_unstemmed |
Mutations in Main Protease of SARS CoV-2 Decreased Boceprevir Affinity |
title_sort |
Mutations in Main Protease of SARS CoV-2 Decreased Boceprevir Affinity |
author |
Akbulut,Ekrem |
author_facet |
Akbulut,Ekrem |
author_role |
author |
dc.contributor.author.fl_str_mv |
Akbulut,Ekrem |
dc.subject.por.fl_str_mv |
boceprevir affinity drug validity main protease mutation SARS-CoV-2 |
topic |
boceprevir affinity drug validity main protease mutation SARS-CoV-2 |
description |
Abstract The coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a global health emergency. The main protease (Mpro) is crucial for the life cycle of coronaviruses. Boceprevir is a potential inhibitor and drug candidate for the Mpro of SARS-CoV-2. In this study, changes in the protein structure of the Mpro due to mutations in SARS-CoV-2 and the effects of these changes on boceprevir affinity, an important potential therapeutic agent, were investigated. The mutations were analyzed with RDP4 and MegaX. A three-dimensional model of mutant Mpro was generated by ProMod3. Qualitative Model Energy Analysis, ProSA, and MolProbity tools were used for structural validation and modeling of the wild-type and mutant Mpro proteins. Topological differences of the wild-type and mutant Mpro were calculated with the i-Tasser TM-Score. Molecular docking was performed using AutoDock 4.2. Functional dynamic structure models were created with DynOmics. Seven mutations (L89F, K90R, P108S, A191V, T224A, A234V and S254F) were detected in the Mpro of SARS-CoV-2. The mutations caused a decrease in the affinity of boceprevir, a potential protease inhibitor. The boceprevir was docked to the active site of Mpro, and the binding energies were −10.34 and −9.41 kcal.mol-1 for the wild-type and the mutant, respectively. The Debye-Waller factors calculated by elastic network model analysis were 0.58 and 0.64 Å2 for the wild-type Mpro and mutant Mpro, respectively. Mutations in structures that are important drug targets for SARS-CoV-2 may render existing therapeutics ineffective in its treatment. |
publishDate |
2021 |
dc.date.none.fl_str_mv |
2021-01-01 |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/article |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
format |
article |
status_str |
publishedVersion |
dc.identifier.uri.fl_str_mv |
http://old.scielo.br/scielo.php?script=sci_arttext&pid=S1516-89132021000100434 |
url |
http://old.scielo.br/scielo.php?script=sci_arttext&pid=S1516-89132021000100434 |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
10.1590/1678-4324-2021200803 |
dc.rights.driver.fl_str_mv |
info:eu-repo/semantics/openAccess |
eu_rights_str_mv |
openAccess |
dc.format.none.fl_str_mv |
text/html |
dc.publisher.none.fl_str_mv |
Instituto de Tecnologia do Paraná - Tecpar |
publisher.none.fl_str_mv |
Instituto de Tecnologia do Paraná - Tecpar |
dc.source.none.fl_str_mv |
Brazilian Archives of Biology and Technology v.64 2021 reponame:Brazilian Archives of Biology and Technology instname:Instituto de Tecnologia do Paraná (Tecpar) instacron:TECPAR |
instname_str |
Instituto de Tecnologia do Paraná (Tecpar) |
instacron_str |
TECPAR |
institution |
TECPAR |
reponame_str |
Brazilian Archives of Biology and Technology |
collection |
Brazilian Archives of Biology and Technology |
repository.name.fl_str_mv |
Brazilian Archives of Biology and Technology - Instituto de Tecnologia do Paraná (Tecpar) |
repository.mail.fl_str_mv |
babt@tecpar.br||babt@tecpar.br |
_version_ |
1750318280847917056 |