CICLODEXTRINAS COMO CARREADORES DE FÁRMACOS PARA SISTEMA NERVOSO CENTRAL VIA MODELAGEM MOLECULAR

Detalhes bibliográficos
Autor(a) principal: Vendrame, Laura Fernanda Osmari
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.
id UFN-1_19c0b1ddb2ff32c9ecbad657ed5535f8
oai_identifier_str oai:tede.universidadefranciscana.edu.br:UFN-BDTD/844
network_acronym_str UFN-1
network_name_str Repositório Institucional Universidade Franciscana
repository_id_str http://www.tede.universidadefranciscana.edu.br:8080/oai/request
spelling 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). No. of bitstreams: 2 Tese_LauraFernandaOsmariVendrame.pdf: 4346466 bytes, checksum: 99dc4fc65cfba0aff13fc650fb9673de (MD5) license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) Previous issue date: 2019-03-29CAPESapplication/pdfhttp://www.tede.universidadefranciscana.edu.br:8080/retrieve/5657/Tese_LauraFernandaOsmariVendrame.pdf.jpgporUniversidade FranciscanaPrograma de Pós-Graduação em NanociênciasUFNBrasilBiociências e Nanomateriaishttp://creativecommons.org/licenses/by-nc-nd/4.0/info:eu-repo/semantics/embargoedAccessDFT, Docagem Molecular, Ciclodextrina, GROMOS, Sistema Nervoso Central.DFT, Molecular Docking, Cyclodextrin, GROMOS, Central Nervous SystemNanociênciasCICLODEXTRINAS COMO CARREADORES DE FÁRMACOS PARA SISTEMA NERVOSO CENTRAL VIA MODELAGEM MOLECULARinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/doctoralThesisreponame:Repositório Institucional Universidade Franciscanainstname:Universidade Franciscana (UFN)instacron:UFNTHUMBNAILTese_LauraFernandaOsmariVendrame.pdf.jpgTese_LauraFernandaOsmariVendrame.pdf.jpgimage/jpeg4637http://tede.universidadefranciscana.edu.br:8080/bitstream/UFN-BDTD/844/7/Tese_LauraFernandaOsmariVendrame.pdf.jpgfdc0f20d2d00ae28fc259437f018b023MD57TEXTTese_LauraFernandaOsmariVendrame.pdf.txtTese_LauraFernandaOsmariVendrame.pdf.txttext/plain176978http://tede.universidadefranciscana.edu.br:8080/bitstream/UFN-BDTD/844/6/Tese_LauraFernandaOsmariVendrame.pdf.txtb7f184ec2f1060095c9826645eb7c122MD56ORIGINALTese_LauraFernandaOsmariVendrame.pdfTese_LauraFernandaOsmariVendrame.pdfapplication/pdf4346466http://tede.universidadefranciscana.edu.br:8080/bitstream/UFN-BDTD/844/5/Tese_LauraFernandaOsmariVendrame.pdf99dc4fc65cfba0aff13fc650fb9673deMD55CC-LICENSElicense_urllicense_urltext/plain; charset=utf-849http://tede.universidadefranciscana.edu.br:8080/bitstream/UFN-BDTD/844/2/license_url4afdbb8c545fd630ea7db775da747b2fMD52license_textlicense_texttext/html; charset=utf-80http://tede.universidadefranciscana.edu.br:8080/bitstream/UFN-BDTD/844/3/license_textd41d8cd98f00b204e9800998ecf8427eMD53license_rdflicense_rdfapplication/rdf+xml; charset=utf-80http://tede.universidadefranciscana.edu.br:8080/bitstream/UFN-BDTD/844/4/license_rdfd41d8cd98f00b204e9800998ecf8427eMD54LICENSElicense.txtlicense.txttext/plain; charset=utf-8310http://tede.universidadefranciscana.edu.br:8080/bitstream/UFN-BDTD/844/1/license.txt7dc66ddb96829ff34b56b1a92c851bcdMD51UFN-BDTD/8442019-12-07 01:00:44.595oai:tede.universidadefranciscana.edu.br:UFN-BDTD/844RXN0ZSB0cmFiYWxobyBzZXLDoSBsaWNlbmNpYWRvIHNvYiBhIExpY2Vuw6dhIEF0cmlidWnDp8Ojby1Ow6NvQ29tZXJjaWFsLVNlbURlcml2YcOnw7VlcyA0LjAgSW50ZXJuYWNpb25hbCBDcmVhdGl2ZSBDb21tb25zLiBQYXJhIHZpc3VhbGl6YXIgdW1hIGPDs3BpYSBkZXN0YSBsaWNlbsOnYSwgdmlzaXRlIGh0dHA6Ly9jcmVhdGl2ZWNvbW1vbnMub3JnL2xpY2Vuc2VzL2J5LW5jLW5kLzQuMC8gb3UgbWFuZGUgdW1hIGNhcnRhIHBhcmEgQ3JlYXRpdmUgQ29tbW9ucywgUE8gQm94IDE4NjYsIE1vdW50YWluIFZpZXcsIENBIDk0MDQyLCBVU0EuCg==Repositório de Publicaçõeshttp://www.tede.universidadefranciscana.edu.br:8080/http://www.tede.universidadefranciscana.edu.br:8080/oai/requestopendoar:2019-12-07T03:00:44Repositório Institucional Universidade Franciscana - Universidade Franciscana (UFN)false
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
rights_invalid_str_mv http://creativecommons.org/licenses/by-nc-nd/4.0/
eu_rights_str_mv embargoedAccess
dc.format.none.fl_str_mv 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
publisher.none.fl_str_mv Universidade Franciscana
dc.source.none.fl_str_mv reponame:Repositório Institucional Universidade Franciscana
instname:Universidade Franciscana (UFN)
instacron:UFN
instname_str Universidade Franciscana (UFN)
instacron_str UFN
institution UFN
reponame_str Repositório Institucional Universidade Franciscana
collection Repositório Institucional Universidade Franciscana
bitstream.url.fl_str_mv http://tede.universidadefranciscana.edu.br:8080/bitstream/UFN-BDTD/844/7/Tese_LauraFernandaOsmariVendrame.pdf.jpg
http://tede.universidadefranciscana.edu.br:8080/bitstream/UFN-BDTD/844/6/Tese_LauraFernandaOsmariVendrame.pdf.txt
http://tede.universidadefranciscana.edu.br:8080/bitstream/UFN-BDTD/844/5/Tese_LauraFernandaOsmariVendrame.pdf
http://tede.universidadefranciscana.edu.br:8080/bitstream/UFN-BDTD/844/2/license_url
http://tede.universidadefranciscana.edu.br:8080/bitstream/UFN-BDTD/844/3/license_text
http://tede.universidadefranciscana.edu.br:8080/bitstream/UFN-BDTD/844/4/license_rdf
http://tede.universidadefranciscana.edu.br:8080/bitstream/UFN-BDTD/844/1/license.txt
bitstream.checksum.fl_str_mv fdc0f20d2d00ae28fc259437f018b023
b7f184ec2f1060095c9826645eb7c122
99dc4fc65cfba0aff13fc650fb9673de
4afdbb8c545fd630ea7db775da747b2f
d41d8cd98f00b204e9800998ecf8427e
d41d8cd98f00b204e9800998ecf8427e
7dc66ddb96829ff34b56b1a92c851bcd
bitstream.checksumAlgorithm.fl_str_mv MD5
MD5
MD5
MD5
MD5
MD5
MD5
repository.name.fl_str_mv Repositório Institucional Universidade Franciscana - Universidade Franciscana (UFN)
repository.mail.fl_str_mv
_version_ 1809269402831421440