CICLODEXTRINAS COMO CARREADORES DE FÁRMACOS PARA SISTEMA NERVOSO CENTRAL VIA MODELAGEM MOLECULAR
Autor(a) principal: | |
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Data de Publicação: | 2019 |
Tipo de documento: | Tese |
Idioma: | por |
Título da fonte: | Repositório Institucional Universidade Franciscana |
Texto Completo: | http://www.tede.universidadefranciscana.edu.br:8080/handle/UFN-BDTD/844 |
Resumo: | In this thesis, the study of cyclodextrin (CDs), as a carrier for the Central Nervous System (CNS) is studied through quantum initiation calculations, molecular docking and molecular dynamics. The chemotherapeutic methotrexate is also studied, with its CD complex being evaluated, as well as receptor-ligand studies with the P-glycoprotein due to its ability to expel drugs from the CNS. Methotrexate is hydrophilic and anticancer, widely used in CNS neoplasms. However, its low permeability in the blood / brain barrier and high toxicity make further studies for the use of this drug important. The association of this chemotherapeutic with nanostructures such as cyclodextrins (CDs) and the P-glycoprotein is an important study that aims to contribute to studies to increase its delivery in the CNS and decrease its toxic effects. At first, it's presented in this work the results in DFT which are promissing in regards of MTX-CD delivery to the NCS, since we want the drug to be in the cyclodextrin cavity due to its hydrophobic interior and hydrophilic exterior without occurring covalent bonds that change the drug's active principle making it difficult to release at the target site. Second, the study of molecular docking in the present work on CDs with P-glycoprotein may open the way for the use of CDs in studies for the CNS to make regulatory decisions on drug delivery, allowing the prediction of potential impacts on treatments for the CNS. Finally, the work done with the GROMACS program constitutes a benchmark for future studies based on the GROMOS force field, suggesting its potential for MTX and condensed-phase β-CD studies. It also opens the perspective of the use of new techniques of molecular and metadynamic dynamics, with these parameters, in the study of the conformational profile, dynamics and flexibility of drugs in solution. |
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Silva, Ivana Zanella daVerli, HugoJauris, Iuri MedeirosSilva, Leandro Barros daSagrillo, Michele RoratoSouza, Diego deVendrame, Laura Fernanda Osmari2019-12-06T14:16:30Z2020-07-312019-03-29Vendrame, Laura Fernanda Osmari. CICLODEXTRINAS COMO CARREADORES DE FÁRMACOS PARA SISTEMA NERVOSO CENTRAL VIA MODELAGEM MOLECULAR. 2019. 121f. Tese( Programa de Pós-Graduação em Nanociências) - Universidade Franciscana, Santa Maria - RS .http://www.tede.universidadefranciscana.edu.br:8080/handle/UFN-BDTD/844In this thesis, the study of cyclodextrin (CDs), as a carrier for the Central Nervous System (CNS) is studied through quantum initiation calculations, molecular docking and molecular dynamics. The chemotherapeutic methotrexate is also studied, with its CD complex being evaluated, as well as receptor-ligand studies with the P-glycoprotein due to its ability to expel drugs from the CNS. Methotrexate is hydrophilic and anticancer, widely used in CNS neoplasms. However, its low permeability in the blood / brain barrier and high toxicity make further studies for the use of this drug important. The association of this chemotherapeutic with nanostructures such as cyclodextrins (CDs) and the P-glycoprotein is an important study that aims to contribute to studies to increase its delivery in the CNS and decrease its toxic effects. At first, it's presented in this work the results in DFT which are promissing in regards of MTX-CD delivery to the NCS, since we want the drug to be in the cyclodextrin cavity due to its hydrophobic interior and hydrophilic exterior without occurring covalent bonds that change the drug's active principle making it difficult to release at the target site. Second, the study of molecular docking in the present work on CDs with P-glycoprotein may open the way for the use of CDs in studies for the CNS to make regulatory decisions on drug delivery, allowing the prediction of potential impacts on treatments for the CNS. Finally, the work done with the GROMACS program constitutes a benchmark for future studies based on the GROMOS force field, suggesting its potential for MTX and condensed-phase β-CD studies. It also opens the perspective of the use of new techniques of molecular and metadynamic dynamics, with these parameters, in the study of the conformational profile, dynamics and flexibility of drugs in solution.Nesta tese o estudo de ciclodextrinas (CDs) como um carreador para o Sistema Nervoso Central (SNC) é realizado por meio de cálculos quânticos, docking molecular e dinâmica molecular clássica. O quimioterápico Metotrexato (MTX) é estudado, sendo avaliado seu complexo com CDs e estudos receptor-ligante com a glicoproteína P (Gp-P). Metotrexato é um anticancerígeno, amplamente utilizado nas neoplasias do SNC e apresenta um caráter hidrofílico, o que dificulta sua capacidade de solubilização. Sua baixa permeabilidade na barreira sangue/cérebro e alta toxicidade fazem com que novos estudos para a utilização deste fármaco sejam importantes. A associação deste quimioterápico com nanoestruturas como ciclodextrinas (CDs) e com a P-gp é um estudo importante que visa contribuir em estudos para aumentar sua entrega no SNC e diminuir seus efeitos tóxicos. Em um primeiro momento nesta tese está sendo apresentado um estudo pela Teoria do Funcional da Densidade (DFT) dos complexos MTX com CDs. Os resultados deste trabalho demonstraram que as configurações mais estáveis são aquelas onde o fármaco esteve o mais interno possível na cavidade da ciclodextrina. As interações ocorrem em um processo de adsorção física sem a presença de ligações covalentes que possam mudar o princípio ativo do fármaco e dificultar a liberação no local alvo. Em um segundo momento, foi realizado um estudo de docking molecular de CDs com a Gp-P. Os resultados deste trabalho demonstram que todas a CDs estudadas (α, β e γ-CD) são potenciais ligantes para a Gp-P, podendo abrir caminho para o uso de CDs em estudos para o SNC para tomar decisões regulatórias na entrega de fármacos, permitindo a previsão de potenciais impactos em tratamentos para o SNC. Por último, os trabalhos realizados em dinâmica molecular com o programa GROMACS demonstraram que as conformações mais estaveis em solução são aquelas onde o MTX esteve o mais interno possível da cavidade da CD nos estudos com docking molecular. Além disso, estes resultados constituem-se em um benchmark para futuros estudos baseados no campo de força GROMOS, sugerindo seu potencial para estudos do MTX e β-CD. Abre-se, ainda, a perspectiva de emprego de novas técnicas de dinâmica molecular e metadinâmica com estes parâmetros, no estudo do perfil conformacional, dinâmica e flexibilidade de fármacos em solução.Submitted by MARCIA ROVADOSCHI (marciar@unifra.br) on 2019-12-06T14:16:30Z No. of bitstreams: 2 Tese_LauraFernandaOsmariVendrame.pdf: 4346466 bytes, checksum: 99dc4fc65cfba0aff13fc650fb9673de (MD5) license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5)Made available in DSpace on 2019-12-06T14:16:30Z (GMT). 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dc.title.por.fl_str_mv |
CICLODEXTRINAS COMO CARREADORES DE FÁRMACOS PARA SISTEMA NERVOSO CENTRAL VIA MODELAGEM MOLECULAR |
title |
CICLODEXTRINAS COMO CARREADORES DE FÁRMACOS PARA SISTEMA NERVOSO CENTRAL VIA MODELAGEM MOLECULAR |
spellingShingle |
CICLODEXTRINAS COMO CARREADORES DE FÁRMACOS PARA SISTEMA NERVOSO CENTRAL VIA MODELAGEM MOLECULAR Vendrame, Laura Fernanda Osmari DFT, Docagem Molecular, Ciclodextrina, GROMOS, Sistema Nervoso Central. DFT, Molecular Docking, Cyclodextrin, GROMOS, Central Nervous System Nanociências |
title_short |
CICLODEXTRINAS COMO CARREADORES DE FÁRMACOS PARA SISTEMA NERVOSO CENTRAL VIA MODELAGEM MOLECULAR |
title_full |
CICLODEXTRINAS COMO CARREADORES DE FÁRMACOS PARA SISTEMA NERVOSO CENTRAL VIA MODELAGEM MOLECULAR |
title_fullStr |
CICLODEXTRINAS COMO CARREADORES DE FÁRMACOS PARA SISTEMA NERVOSO CENTRAL VIA MODELAGEM MOLECULAR |
title_full_unstemmed |
CICLODEXTRINAS COMO CARREADORES DE FÁRMACOS PARA SISTEMA NERVOSO CENTRAL VIA MODELAGEM MOLECULAR |
title_sort |
CICLODEXTRINAS COMO CARREADORES DE FÁRMACOS PARA SISTEMA NERVOSO CENTRAL VIA MODELAGEM MOLECULAR |
author |
Vendrame, Laura Fernanda Osmari |
author_facet |
Vendrame, Laura Fernanda Osmari |
author_role |
author |
dc.contributor.advisor1.fl_str_mv |
Silva, Ivana Zanella da |
dc.contributor.advisor-co1.fl_str_mv |
Verli, Hugo |
dc.contributor.referee1.fl_str_mv |
Jauris, Iuri Medeiros |
dc.contributor.referee2.fl_str_mv |
Silva, Leandro Barros da |
dc.contributor.referee3.fl_str_mv |
Sagrillo, Michele Rorato |
dc.contributor.referee4.fl_str_mv |
Souza, Diego de |
dc.contributor.author.fl_str_mv |
Vendrame, Laura Fernanda Osmari |
contributor_str_mv |
Silva, Ivana Zanella da Verli, Hugo Jauris, Iuri Medeiros Silva, Leandro Barros da Sagrillo, Michele Rorato Souza, Diego de |
dc.subject.por.fl_str_mv |
DFT, Docagem Molecular, Ciclodextrina, GROMOS, Sistema Nervoso Central. |
topic |
DFT, Docagem Molecular, Ciclodextrina, GROMOS, Sistema Nervoso Central. DFT, Molecular Docking, Cyclodextrin, GROMOS, Central Nervous System Nanociências |
dc.subject.eng.fl_str_mv |
DFT, Molecular Docking, Cyclodextrin, GROMOS, Central Nervous System |
dc.subject.cnpq.fl_str_mv |
Nanociências |
description |
In this thesis, the study of cyclodextrin (CDs), as a carrier for the Central Nervous System (CNS) is studied through quantum initiation calculations, molecular docking and molecular dynamics. The chemotherapeutic methotrexate is also studied, with its CD complex being evaluated, as well as receptor-ligand studies with the P-glycoprotein due to its ability to expel drugs from the CNS. Methotrexate is hydrophilic and anticancer, widely used in CNS neoplasms. However, its low permeability in the blood / brain barrier and high toxicity make further studies for the use of this drug important. The association of this chemotherapeutic with nanostructures such as cyclodextrins (CDs) and the P-glycoprotein is an important study that aims to contribute to studies to increase its delivery in the CNS and decrease its toxic effects. At first, it's presented in this work the results in DFT which are promissing in regards of MTX-CD delivery to the NCS, since we want the drug to be in the cyclodextrin cavity due to its hydrophobic interior and hydrophilic exterior without occurring covalent bonds that change the drug's active principle making it difficult to release at the target site. Second, the study of molecular docking in the present work on CDs with P-glycoprotein may open the way for the use of CDs in studies for the CNS to make regulatory decisions on drug delivery, allowing the prediction of potential impacts on treatments for the CNS. Finally, the work done with the GROMACS program constitutes a benchmark for future studies based on the GROMOS force field, suggesting its potential for MTX and condensed-phase β-CD studies. It also opens the perspective of the use of new techniques of molecular and metadynamic dynamics, with these parameters, in the study of the conformational profile, dynamics and flexibility of drugs in solution. |
publishDate |
2019 |
dc.date.accessioned.fl_str_mv |
2019-12-06T14:16:30Z |
dc.date.issued.fl_str_mv |
2019-03-29 |
dc.date.available.fl_str_mv |
2020-07-31 |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/doctoralThesis |
format |
doctoralThesis |
status_str |
publishedVersion |
dc.identifier.citation.fl_str_mv |
Vendrame, Laura Fernanda Osmari. CICLODEXTRINAS COMO CARREADORES DE FÁRMACOS PARA SISTEMA NERVOSO CENTRAL VIA MODELAGEM MOLECULAR. 2019. 121f. Tese( Programa de Pós-Graduação em Nanociências) - Universidade Franciscana, Santa Maria - RS . |
dc.identifier.uri.fl_str_mv |
http://www.tede.universidadefranciscana.edu.br:8080/handle/UFN-BDTD/844 |
identifier_str_mv |
Vendrame, Laura Fernanda Osmari. CICLODEXTRINAS COMO CARREADORES DE FÁRMACOS PARA SISTEMA NERVOSO CENTRAL VIA MODELAGEM MOLECULAR. 2019. 121f. Tese( Programa de Pós-Graduação em Nanociências) - Universidade Franciscana, Santa Maria - RS . |
url |
http://www.tede.universidadefranciscana.edu.br:8080/handle/UFN-BDTD/844 |
dc.language.iso.fl_str_mv |
por |
language |
por |
dc.rights.driver.fl_str_mv |
http://creativecommons.org/licenses/by-nc-nd/4.0/ info:eu-repo/semantics/embargoedAccess |
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http://creativecommons.org/licenses/by-nc-nd/4.0/ |
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embargoedAccess |
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application/pdf |
dc.publisher.none.fl_str_mv |
Universidade Franciscana |
dc.publisher.program.fl_str_mv |
Programa de Pós-Graduação em Nanociências |
dc.publisher.initials.fl_str_mv |
UFN |
dc.publisher.country.fl_str_mv |
Brasil |
dc.publisher.department.fl_str_mv |
Biociências e Nanomateriais |
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Universidade Franciscana |
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