Development of New Potential Inhibitors of 1 Integrins through In Silico Methods—Screening and Computational Validation

Detalhes bibliográficos
Autor(a) principal: Vasconcelos, Disraeli
Data de Publicação: 2022
Outros Autores: Chaves, Beatriz, Albuquerque, Aline, Andrade, Luca, Henriques, Andrielly, Sartori, Geraldo, Savino, Wilson, Caffarena, Ernesto, Silva, João Herminio Martins da
Tipo de documento: Artigo
Idioma: eng
Título da fonte: Repositório Institucional da FIOCRUZ (ARCA)
Texto Completo: https://www.arca.fiocruz.br/handle/icict/54880
Resumo: Fundação Oswaldo Cruz. Fiocruz Ceará. Laboratório de Biologia Estrutural e Funcional em Biofármacos. Eusébio, CE, Brasil.
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spelling Vasconcelos, DisraeliChaves, BeatrizAlbuquerque, AlineAndrade, LucaHenriques, AndriellySartori, GeraldoSavino, WilsonCaffarena, ErnestoSilva, João Herminio Martins da2022-09-27T14:16:09Z2022-09-27T14:16:09Z2022DISRAELI, Vasconcelos et al. Development of New Potential Inhibitors of β1 Integrins through In Silico Methods—Screening and Computational Validation. Life , 12, 932, 2022.2075-1729https://www.arca.fiocruz.br/handle/icict/5488010.3390/life12070932engMDPIDevelopment of New Potential Inhibitors of 1 Integrins through In Silico Methods—Screening and Computational Validationinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleFundação Oswaldo Cruz. Fiocruz Ceará. Laboratório de Biologia Estrutural e Funcional em Biofármacos. Eusébio, CE, Brasil.Fundação Oswaldo Cruz. Fiocruz Ceará. Laboratório de Biologia Estrutural e Funcional em Biofármacos. Eusébio, CE, Brasil.Fundação Oswaldo Cruz. Fiocruz Ceará. Laboratório de Biologia Estrutural e Funcional em Biofármacos. Eusébio, CE, Brasil.Fundação Oswaldo Cruz. Fiocruz Ceará. Laboratório de Biologia Estrutural e Funcional em Biofármacos. Eusébio, CE, Brasil.Fundação Oswaldo Cruz. Fiocruz Ceará. Laboratório de Biologia Estrutural e Funcional em Biofármacos. Eusébio, CE, Brasil.Fundação Oswaldo Cruz. Fiocruz Ceará. Laboratório de Biologia Estrutural e Funcional em Biofármacos. Eusébio, CE, Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz, Rio de Janeiro, Brasil.Fundação Oswaldo Cruz. Presidência. Programa de Computação Científica. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Fiocruz Ceará. Eusébio, CE, Brasil / Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Rio de Janeiro, Brasil.Integrins are transmembrane receptors that play a critical role in many biological processes which can be therapeutically modulated using integrin blockers, such as peptidomimetic ligands. This work aimed to develop new potential β1 integrin antagonists using modeled receptors based on the aligned crystallographic structures and docked with three lead compounds (BIO1211, BIO5192, and TCS2314), widely known as α4β1 antagonists. Lead-compound complex optimization was performed by keeping intact the carboxylate moiety of the ligand, adding substituents in two other regions of the molecule to increase the affinity with the target. Additionally, pharmacokinetic predictions were performed for the ten best ligands generated, with the lowest docking interaction energy obtained for α4β1 and BIO5192. Results revealed an essential salt bridge between the BIO5192 carboxylate group and the Mg2+ MIDAS ion of the integrin. We then generated more than 200 new BIO5192 derivatives, some with a greater predicted affinity to α4β1. Furthermore, the significance of retaining the pyrrolidine core of the ligand and increasing the therapeutic potential of the new compounds is emphasized. Finally, one novel molecule (1592) was identified as a potential drug candidate, with appropriate pharmacokinetic profiles, similar dynamic behavior at the integrin interaction site compared with BIO5192, and a higher predicted affinity to VLA-4.IntegrinVLA-4Peptidomimetic inhibitorsMolecular dockingde novo designMolecular dynamicsLead optimizationADMETMM/PBSAinfo:eu-repo/semantics/openAccessreponame:Repositório Institucional da FIOCRUZ (ARCA)instname:Fundação Oswaldo Cruz (FIOCRUZ)instacron:FIOCRUZORIGINALWilsonSavino_etal_IOC_2022.pdfWilsonSavino_etal_IOC_2022.pdfapplication/pdf4276565https://www.arca.fiocruz.br/bitstream/icict/54880/2/WilsonSavino_etal_IOC_2022.pdf87c71c108f692abfd0803667405fde41MD52LICENSElicense.txtlicense.txttext/plain; charset=utf-82991https://www.arca.fiocruz.br/bitstream/icict/54880/3/license.txt5a560609d32a3863062d77ff32785d58MD53icict/548802023-09-04 11:29:53.821oai:www.arca.fiocruz.br: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ório 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dc.title.en_US.fl_str_mv Development of New Potential Inhibitors of 1 Integrins through In Silico Methods—Screening and Computational Validation
title Development of New Potential Inhibitors of 1 Integrins through In Silico Methods—Screening and Computational Validation
spellingShingle Development of New Potential Inhibitors of 1 Integrins through In Silico Methods—Screening and Computational Validation
Vasconcelos, Disraeli
Integrin
VLA-4
Peptidomimetic inhibitors
Molecular docking
de novo design
Molecular dynamics
Lead optimization
ADMET
MM/PBSA
title_short Development of New Potential Inhibitors of 1 Integrins through In Silico Methods—Screening and Computational Validation
title_full Development of New Potential Inhibitors of 1 Integrins through In Silico Methods—Screening and Computational Validation
title_fullStr Development of New Potential Inhibitors of 1 Integrins through In Silico Methods—Screening and Computational Validation
title_full_unstemmed Development of New Potential Inhibitors of 1 Integrins through In Silico Methods—Screening and Computational Validation
title_sort Development of New Potential Inhibitors of 1 Integrins through In Silico Methods—Screening and Computational Validation
author Vasconcelos, Disraeli
author_facet Vasconcelos, Disraeli
Chaves, Beatriz
Albuquerque, Aline
Andrade, Luca
Henriques, Andrielly
Sartori, Geraldo
Savino, Wilson
Caffarena, Ernesto
Silva, João Herminio Martins da
author_role author
author2 Chaves, Beatriz
Albuquerque, Aline
Andrade, Luca
Henriques, Andrielly
Sartori, Geraldo
Savino, Wilson
Caffarena, Ernesto
Silva, João Herminio Martins da
author2_role author
author
author
author
author
author
author
author
dc.contributor.author.fl_str_mv Vasconcelos, Disraeli
Chaves, Beatriz
Albuquerque, Aline
Andrade, Luca
Henriques, Andrielly
Sartori, Geraldo
Savino, Wilson
Caffarena, Ernesto
Silva, João Herminio Martins da
dc.subject.en.en_US.fl_str_mv Integrin
VLA-4
Peptidomimetic inhibitors
Molecular docking
de novo design
Molecular dynamics
Lead optimization
ADMET
MM/PBSA
topic Integrin
VLA-4
Peptidomimetic inhibitors
Molecular docking
de novo design
Molecular dynamics
Lead optimization
ADMET
MM/PBSA
description Fundação Oswaldo Cruz. Fiocruz Ceará. Laboratório de Biologia Estrutural e Funcional em Biofármacos. Eusébio, CE, Brasil.
publishDate 2022
dc.date.accessioned.fl_str_mv 2022-09-27T14:16:09Z
dc.date.available.fl_str_mv 2022-09-27T14:16:09Z
dc.date.issued.fl_str_mv 2022
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 DISRAELI, Vasconcelos et al. Development of New Potential Inhibitors of β1 Integrins through In Silico Methods—Screening and Computational Validation. Life , 12, 932, 2022.
dc.identifier.uri.fl_str_mv https://www.arca.fiocruz.br/handle/icict/54880
dc.identifier.issn.en_US.fl_str_mv 2075-1729
dc.identifier.doi.none.fl_str_mv 10.3390/life12070932
identifier_str_mv DISRAELI, Vasconcelos et al. Development of New Potential Inhibitors of β1 Integrins through In Silico Methods—Screening and Computational Validation. Life , 12, 932, 2022.
2075-1729
10.3390/life12070932
url https://www.arca.fiocruz.br/handle/icict/54880
dc.language.iso.fl_str_mv eng
language eng
dc.rights.driver.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv MDPI
publisher.none.fl_str_mv MDPI
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/54880/2/WilsonSavino_etal_IOC_2022.pdf
https://www.arca.fiocruz.br/bitstream/icict/54880/3/license.txt
bitstream.checksum.fl_str_mv 87c71c108f692abfd0803667405fde41
5a560609d32a3863062d77ff32785d58
bitstream.checksumAlgorithm.fl_str_mv MD5
MD5
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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