Kinase Inhibitor Profile for Human Nek1, Nek6, and Nek7 and Analysis of the Structural Basis for Inhibitor Specificity

Detalhes bibliográficos
Autor(a) principal: Moraes, Eduardo
Data de Publicação: 2015
Outros Autores: Meirelles, Gabriela, Honorato, Rodrigo, Souza, Tatiana de Arruda Campos Brasil de, Souza, Edmarcia de, Murakami, Mario Tyago, Oliveira, Paulo de, Kobarg, Jörg
Tipo de documento: Artigo
Idioma: por
Título da fonte: Repositório Institucional da FIOCRUZ (ARCA)
Texto Completo: https://www.arca.fiocruz.br/handle/icict/15541
Resumo: This study was financiallysupportedby Grant 2010/51730-0 from São Paulo Research Foundation (FAPESP), ConselhoNacional de Pesquisa e Desenvolvimento (CNPq) and Centro Nacional de PesquisaemEnergia e Materiais (CNPEM).
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spelling Moraes, EduardoMeirelles, GabrielaHonorato, RodrigoSouza, Tatiana de Arruda Campos Brasil deSouza, Edmarcia deMurakami, Mario TyagoOliveira, Paulo deKobarg, Jörg2016-08-30T16:15:21Z2016-08-30T16:15:21Z2015MORAES, Eduardo Cruz et al. Kinase Inhibitor Profile for Human Nek1, Nek6, and Nek7 and Analysis of the Structural Basis for Inhibitor Specificity. Molecules, n.20, p. 1176-1191, 2015.1420-3049https://www.arca.fiocruz.br/handle/icict/15541This study was financiallysupportedby Grant 2010/51730-0 from São Paulo Research Foundation (FAPESP), ConselhoNacional de Pesquisa e Desenvolvimento (CNPq) and Centro Nacional de PesquisaemEnergia e Materiais (CNPEM).Centro Nacional de Pesquisa em Energia e Materiais. Laboratório Nacional de Biociências. Campinas, SP, Brasil. / Universidade Estadual de Campinas. Instituto de Biologia. Departamento de Bioquímica e Biologia Tecidual. Programa de Pós-Graduação em Biologia Funcional e Molecular, Campinas, SP, Brasil.Centro Nacional de Pesquisa em Energia e Materiais. Laboratório Nacional de Biociências. Campinas, SP, Brasil. / Universidade Estadual de Campinas. Instituto de Biologia. Departamento de Bioquímica e Biologia Tecidual. Programa de Pós-Graduação em Biologia Funcional e Molecular, Campinas, SP, Brasil.Centro Nacional de Pesquisa em Energia e Materiais. Laboratório Nacional de Biociências. Campinas, SP, Brasil.Fundação Oswaldo Cruz. Instituto Carlos Chagas. Curitiba, PR, Brasil.Centro Nacional de Pesquisa em Energia e Materiais. Laboratório Nacional de Biociências. Campinas, SP, Brasil. / Universidade Estadual de Campinas. Instituto de Biologia. Departamento de Bioquímica e Biologia Tecidual. Programa de Pós-Graduação em Biologia Funcional e Molecular, Campinas, SP, Brasil.Centro Nacional de Pesquisa em Energia e Materiais. Laboratório Nacional de Biociências. Campinas, SP, Brasil.Centro Nacional de Pesquisa em Energia e Materiais. Laboratório Nacional de Biociências. Campinas, SP, Brasil.Universidade Estadual de Campinas. Instituto de Biologia. Departamento de Bioquímica e Biologia Tecidual. Programa de Pós-Graduação em Biologia Funcional e Molecular, Campinas, SP, Brasil. / Universidade Estadual de Campinas. Instituto de Biologia. Departamento de Bioquímica e Biologia Tecidual. Campinas, SP, Brasil. / Universidade Estadual de Campinas. Faculdade de Ciências Farmacêuticas. Campinas, SP, Brasil.Human Neks are a conserved protein kinase family related to cell cycle progression and cell division and are considered potential drug targets for the treatment of cancer and other pathologies. We screened the activation loop mutant kinases hNek1 and hNek2, wild-type hNek7, and five hNek6 variants in different activation/phosphorylation statesand compared them against 85 compounds using thermal shift denaturation. We identified three compounds with significant Tm shifts: JNK Inhibitor II for hNek1(Δ262-1258)-(T162A), Isogranulatimide for hNek6(S206A), andGSK-3 Inhibitor XIII for hNek7wt. Each one of these compounds was also validated by reducing the kinases activity by at least 25%. The binding sites for these compounds were identified by in silico docking at the ATP-binding site of the respective hNeks. Potential inhibitors were first screened by thermal shift assays, had their efficiency tested by a kinase assay, and were finally analyzed by molecular docking. Our findings corroborate the idea of ATP-competitive inhibition for hNek1 and hNek6 and suggest a novel non-competitive inhibition for hNek7 in regard to GSK-3 Inhibitor XIII. Our results demonstrate that our approach is useful for finding promising general and specific hNekscandidate inhibitors, which may also function as scaffolds to design more potent and selective inhibitors.porKinase Inhibitor Profile for Human Nek1, Nek6, and Nek7 and Analysis of the Structural Basis for Inhibitor Specificityinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articledrug discoverycompound screeningkinase assaysmolecular modelingmolecular dockingATP-competitive inhibitorsNon-competitive inhibitionNeksinfo:eu-repo/semantics/openAccessreponame:Repositório Institucional da FIOCRUZ (ARCA)instname:Fundação Oswaldo Cruz (FIOCRUZ)instacron:FIOCRUZLICENSElicense.txtlicense.txttext/plain; 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dc.title.pt_BR.fl_str_mv Kinase Inhibitor Profile for Human Nek1, Nek6, and Nek7 and Analysis of the Structural Basis for Inhibitor Specificity
title Kinase Inhibitor Profile for Human Nek1, Nek6, and Nek7 and Analysis of the Structural Basis for Inhibitor Specificity
spellingShingle Kinase Inhibitor Profile for Human Nek1, Nek6, and Nek7 and Analysis of the Structural Basis for Inhibitor Specificity
Moraes, Eduardo
drug discovery
compound screening
kinase assays
molecular modeling
molecular docking
ATP-competitive inhibitors
Non-competitive inhibition
Neks
title_short Kinase Inhibitor Profile for Human Nek1, Nek6, and Nek7 and Analysis of the Structural Basis for Inhibitor Specificity
title_full Kinase Inhibitor Profile for Human Nek1, Nek6, and Nek7 and Analysis of the Structural Basis for Inhibitor Specificity
title_fullStr Kinase Inhibitor Profile for Human Nek1, Nek6, and Nek7 and Analysis of the Structural Basis for Inhibitor Specificity
title_full_unstemmed Kinase Inhibitor Profile for Human Nek1, Nek6, and Nek7 and Analysis of the Structural Basis for Inhibitor Specificity
title_sort Kinase Inhibitor Profile for Human Nek1, Nek6, and Nek7 and Analysis of the Structural Basis for Inhibitor Specificity
author Moraes, Eduardo
author_facet Moraes, Eduardo
Meirelles, Gabriela
Honorato, Rodrigo
Souza, Tatiana de Arruda Campos Brasil de
Souza, Edmarcia de
Murakami, Mario Tyago
Oliveira, Paulo de
Kobarg, Jörg
author_role author
author2 Meirelles, Gabriela
Honorato, Rodrigo
Souza, Tatiana de Arruda Campos Brasil de
Souza, Edmarcia de
Murakami, Mario Tyago
Oliveira, Paulo de
Kobarg, Jörg
author2_role author
author
author
author
author
author
author
dc.contributor.author.fl_str_mv Moraes, Eduardo
Meirelles, Gabriela
Honorato, Rodrigo
Souza, Tatiana de Arruda Campos Brasil de
Souza, Edmarcia de
Murakami, Mario Tyago
Oliveira, Paulo de
Kobarg, Jörg
dc.subject.en.pt_BR.fl_str_mv drug discovery
compound screening
kinase assays
molecular modeling
molecular docking
ATP-competitive inhibitors
Non-competitive inhibition
Neks
topic drug discovery
compound screening
kinase assays
molecular modeling
molecular docking
ATP-competitive inhibitors
Non-competitive inhibition
Neks
description This study was financiallysupportedby Grant 2010/51730-0 from São Paulo Research Foundation (FAPESP), ConselhoNacional de Pesquisa e Desenvolvimento (CNPq) and Centro Nacional de PesquisaemEnergia e Materiais (CNPEM).
publishDate 2015
dc.date.issued.fl_str_mv 2015
dc.date.accessioned.fl_str_mv 2016-08-30T16:15:21Z
dc.date.available.fl_str_mv 2016-08-30T16:15:21Z
dc.type.status.fl_str_mv info:eu-repo/semantics/publishedVersion
dc.type.driver.fl_str_mv info:eu-repo/semantics/article
format article
status_str publishedVersion
dc.identifier.citation.fl_str_mv MORAES, Eduardo Cruz et al. Kinase Inhibitor Profile for Human Nek1, Nek6, and Nek7 and Analysis of the Structural Basis for Inhibitor Specificity. Molecules, n.20, p. 1176-1191, 2015.
dc.identifier.uri.fl_str_mv https://www.arca.fiocruz.br/handle/icict/15541
dc.identifier.issn.pt_BR.fl_str_mv 1420-3049
identifier_str_mv MORAES, Eduardo Cruz et al. Kinase Inhibitor Profile for Human Nek1, Nek6, and Nek7 and Analysis of the Structural Basis for Inhibitor Specificity. Molecules, n.20, p. 1176-1191, 2015.
1420-3049
url https://www.arca.fiocruz.br/handle/icict/15541
dc.language.iso.fl_str_mv por
language por
dc.rights.driver.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.source.none.fl_str_mv reponame:Repositório Institucional da FIOCRUZ (ARCA)
instname:Fundação Oswaldo Cruz (FIOCRUZ)
instacron:FIOCRUZ
instname_str Fundação Oswaldo Cruz (FIOCRUZ)
instacron_str FIOCRUZ
institution FIOCRUZ
reponame_str Repositório Institucional da FIOCRUZ (ARCA)
collection Repositório Institucional da FIOCRUZ (ARCA)
bitstream.url.fl_str_mv https://www.arca.fiocruz.br/bitstream/icict/15541/1/license.txt
https://www.arca.fiocruz.br/bitstream/icict/15541/2/molecules-20-01176.pdf
https://www.arca.fiocruz.br/bitstream/icict/15541/3/molecules-20-01176.pdf.txt
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repository.name.fl_str_mv Repositório Institucional da FIOCRUZ (ARCA) - Fundação Oswaldo Cruz (FIOCRUZ)
repository.mail.fl_str_mv repositorio.arca@fiocruz.br
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