Development of New Potential Inhibitors of 1 Integrins through In Silico Methods—Screening and Computational Validation
Autor(a) principal: | |
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Data de Publicação: | 2022 |
Outros Autores: | , , , , , , , |
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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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:icict/54880Q0VTU8ODTyBOw4NPIEVYQ0xVU0lWQSBERSBESVJFSVRPUyBBVVRPUkFJUwoKQW8gYWNlaXRhciBvcyBURVJNT1MgZSBDT05EScOHw5VFUyBkZXN0YSBDRVNTw4NPLCBvIEFVVE9SIGUvb3UgVElUVUxBUiBkZSBkaXJlaXRvcwphdXRvcmFpcyBzb2JyZSBhIE9CUkEgZGUgcXVlIHRyYXRhIGVzdGUgZG9jdW1lbnRvOgoKKDEpIENFREUgZSBUUkFOU0ZFUkUsIHRvdGFsIGUgZ3JhdHVpdGFtZW50ZSwgw6AgRklPQ1JVWiAtIEZVTkRBw4fDg08gT1NXQUxETyBDUlVaLCBlbQpjYXLDoXRlciBwZXJtYW5lbnRlLCBpcnJldm9nw6F2ZWwgZSBOw4NPIEVYQ0xVU0lWTywgdG9kb3Mgb3MgZGlyZWl0b3MgcGF0cmltb25pYWlzIE7Dg08KQ09NRVJDSUFJUyBkZSB1dGlsaXphw6fDo28gZGEgT0JSQSBhcnTDrXN0aWNhIGUvb3UgY2llbnTDrWZpY2EgaW5kaWNhZGEgYWNpbWEsIGluY2x1c2l2ZSBvcyBkaXJlaXRvcwpkZSB2b3ogZSBpbWFnZW0gdmluY3VsYWRvcyDDoCBPQlJBLCBkdXJhbnRlIHRvZG8gbyBwcmF6byBkZSBkdXJhw6fDo28gZG9zIGRpcmVpdG9zIGF1dG9yYWlzLCBlbQpxdWFscXVlciBpZGlvbWEgZSBlbSB0b2RvcyBvcyBwYcOtc2VzOwoKKDIpIEFDRUlUQSBxdWUgYSBjZXNzw6NvIHRvdGFsIG7Do28gZXhjbHVzaXZhLCBwZXJtYW5lbnRlIGUgaXJyZXZvZ8OhdmVsIGRvcyBkaXJlaXRvcyBhdXRvcmFpcwpwYXRyaW1vbmlhaXMgbsOjbyBjb21lcmNpYWlzIGRlIHV0aWxpemHDp8OjbyBkZSBxdWUgdHJhdGEgZXN0ZSBkb2N1bWVudG8gaW5jbHVpLCBleGVtcGxpZmljYXRpdmFtZW50ZSwKb3MgZGlyZWl0b3MgZGUgZGlzcG9uaWJpbGl6YcOnw6NvIGUgY29tdW5pY2HDp8OjbyBww7pibGljYSBkYSBPQlJBLCBlbSBxdWFscXVlciBtZWlvIG91IHZlw61jdWxvLAppbmNsdXNpdmUgZW0gUmVwb3NpdMOzcmlvcyBEaWdpdGFpcywgYmVtIGNvbW8gb3MgZGlyZWl0b3MgZGUgcmVwcm9kdcOnw6NvLCBleGliacOnw6NvLCBleGVjdcOnw6NvLApkZWNsYW1hw6fDo28sIHJlY2l0YcOnw6NvLCBleHBvc2nDp8OjbywgYXJxdWl2YW1lbnRvLCBpbmNsdXPDo28gZW0gYmFuY28gZGUgZGFkb3MsIHByZXNlcnZhw6fDo28sIGRpZnVzw6NvLApkaXN0cmlidWnDp8OjbywgZGl2dWxnYcOnw6NvLCBlbXByw6lzdGltbywgdHJhZHXDp8OjbywgZHVibGFnZW0sIGxlZ2VuZGFnZW0sIGluY2x1c8OjbyBlbSBub3ZhcyBvYnJhcyBvdQpjb2xldMOibmVhcywgcmV1dGlsaXphw6fDo28sIGVkacOnw6NvLCBwcm9kdcOnw6NvIGRlIG1hdGVyaWFsIGRpZMOhdGljbyBlIGN1cnNvcyBvdSBxdWFscXVlciBmb3JtYSBkZQp1dGlsaXphw6fDo28gbsOjbyBjb21lcmNpYWw7CgooMykgUkVDT05IRUNFIHF1ZSBhIGNlc3PDo28gYXF1aSBlc3BlY2lmaWNhZGEgY29uY2VkZSDDoCBGSU9DUlVaIC0gRlVOREHDh8ODTyBPU1dBTERPCkNSVVogbyBkaXJlaXRvIGRlIGF1dG9yaXphciBxdWFscXVlciBwZXNzb2Eg4oCTIGbDrXNpY2Egb3UganVyw61kaWNhLCBww7pibGljYSBvdSBwcml2YWRhLCBuYWNpb25hbCBvdQplc3RyYW5nZWlyYSDigJMgYSBhY2Vzc2FyIGUgdXRpbGl6YXIgYW1wbGFtZW50ZSBhIE9CUkEsIHNlbSBleGNsdXNpdmlkYWRlLCBwYXJhIHF1YWlzcXVlcgpmaW5hbGlkYWRlcyBuw6NvIGNvbWVyY2lhaXM7CgooNCkgREVDTEFSQSBxdWUgYSBvYnJhIMOpIGNyaWHDp8OjbyBvcmlnaW5hbCBlIHF1ZSDDqSBvIHRpdHVsYXIgZG9zIGRpcmVpdG9zIGFxdWkgY2VkaWRvcyBlIGF1dG9yaXphZG9zLApyZXNwb25zYWJpbGl6YW5kby1zZSBpbnRlZ3JhbG1lbnRlIHBlbG8gY29udGXDumRvIGUgb3V0cm9zIGVsZW1lbnRvcyBxdWUgZmF6ZW0gcGFydGUgZGEgT0JSQSwKaW5jbHVzaXZlIG9zIGRpcmVpdG9zIGRlIHZveiBlIGltYWdlbSB2aW5jdWxhZG9zIMOgIE9CUkEsIG9icmlnYW5kby1zZSBhIGluZGVuaXphciB0ZXJjZWlyb3MgcG9yCmRhbm9zLCBiZW0gY29tbyBpbmRlbml6YXIgZSByZXNzYXJjaXIgYSBGSU9DUlVaIC0gRlVOREHDh8ODTyBPU1dBTERPIENSVVogZGUKZXZlbnR1YWlzIGRlc3Blc2FzIHF1ZSB2aWVyZW0gYSBzdXBvcnRhciwgZW0gcmF6w6NvIGRlIHF1YWxxdWVyIG9mZW5zYSBhIGRpcmVpdG9zIGF1dG9yYWlzIG91CmRpcmVpdG9zIGRlIHZveiBvdSBpbWFnZW0sIHByaW5jaXBhbG1lbnRlIG5vIHF1ZSBkaXogcmVzcGVpdG8gYSBwbMOhZ2lvIGUgdmlvbGHDp8O1ZXMgZGUgZGlyZWl0b3M7CgooNSkgQUZJUk1BIHF1ZSBjb25oZWNlIGEgUG9sw610aWNhIEluc3RpdHVjaW9uYWwgZGUgQWNlc3NvIEFiZXJ0byBkYSBGSU9DUlVaIC0gRlVOREHDh8ODTwpPU1dBTERPIENSVVogZSBhcyBkaXJldHJpemVzIHBhcmEgbyBmdW5jaW9uYW1lbnRvIGRvIHJlcG9zaXTDs3JpbyBpbnN0aXR1Y2lvbmFsIEFSQ0EuCgpBIFBvbMOtdGljYSBJbnN0aXR1Y2lvbmFsIGRlIEFjZXNzbyBBYmVydG8gZGEgRklPQ1JVWiAtIEZVTkRBw4fDg08gT1NXQUxETyBDUlVaIHJlc2VydmEKZXhjbHVzaXZhbWVudGUgYW8gQVVUT1Igb3MgZGlyZWl0b3MgbW9yYWlzIGUgb3MgdXNvcyBjb21lcmNpYWlzIHNvYnJlIGFzIG9icmFzIGRlIHN1YSBhdXRvcmlhCmUvb3UgdGl0dWxhcmlkYWRlLCBzZW5kbyBvcyB0ZXJjZWlyb3MgdXN1w6FyaW9zIHJlc3BvbnPDoXZlaXMgcGVsYSBhdHJpYnVpw6fDo28gZGUgYXV0b3JpYSBlIG1hbnV0ZW7Dp8OjbwpkYSBpbnRlZ3JpZGFkZSBkYSBPQlJBIGVtIHF1YWxxdWVyIHV0aWxpemHDp8Ojby4KCkEgUG9sw610aWNhIEluc3RpdHVjaW9uYWwgZGUgQWNlc3NvIEFiZXJ0byBkYSBGSU9DUlVaIC0gRlVOREHDh8ODTyBPU1dBTERPIENSVVoKcmVzcGVpdGEgb3MgY29udHJhdG9zIGUgYWNvcmRvcyBwcmVleGlzdGVudGVzIGRvcyBBdXRvcmVzIGNvbSB0ZXJjZWlyb3MsIGNhYmVuZG8gYW9zIEF1dG9yZXMKaW5mb3JtYXIgw6AgSW5zdGl0dWnDp8OjbyBhcyBjb25kacOnw7VlcyBlIG91dHJhcyByZXN0cmnDp8O1ZXMgaW1wb3N0YXMgcG9yIGVzdGVzIGluc3RydW1lbnRvcy4KRepositório 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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 |
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Fundação Oswaldo Cruz (FIOCRUZ) |
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FIOCRUZ |
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FIOCRUZ |
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Repositório Institucional da FIOCRUZ (ARCA) |
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Repositório Institucional da FIOCRUZ (ARCA) |
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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 |
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Repositório Institucional da FIOCRUZ (ARCA) - Fundação Oswaldo Cruz (FIOCRUZ) |
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repositorio.arca@fiocruz.br |
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