The implementation of NMR techniques for measuring interactions between small organic molecules/inhibitors and enzyme Acetylcholinesterase: a step towards Alzheimer´s control
Ano de defesa: | 2015 |
---|---|
Autor(a) principal: | |
Orientador(a): | |
Banca de defesa: | |
Tipo de documento: | Tese |
Tipo de acesso: | Acesso aberto |
Idioma: | eng |
Instituição de defesa: |
Universidade Federal de São Carlos
Câmpus São Carlos |
Programa de Pós-Graduação: |
Programa de Pós-Graduação em Química - PPGQ
|
Departamento: |
Não Informado pela instituição
|
País: |
Não Informado pela instituição
|
Palavras-chave em Português: | |
Palavras-chave em Inglês: | |
Área do conhecimento CNPq: | |
Link de acesso: | https://repositorio.ufscar.br/handle/ufscar/10896 |
Resumo: | The inhibition of the acetylcholinesterase (AChE) might be an excellent therapy in controlling Alzheimer’s disease as stated by the cholinergic hypothesis. In this context, the inhibitors of AChE, are of medical and commercial paramount interest as therapeutics for Alzheimer’s disease and as pesticides. However, the conformational changes in inhibitors with AChE complex facilitate the rational design of some novel inhibitors with increased potency and specificity. Therefore, solution state NMR is a novel approach that seems to fulfil almost all conditions necessary to investigate the AChE-inhibitor complex. In this perspective, a combined strategy of STD, Tr-NOESY, DOSY, and docking simulations were applied to compare the bindings of four synthetic coumarin derivatives to tacrine for their binding potentials. Intriguingly, one of them (compound 1) was found to have not only the stronger affinity than the control but could bind with three sites. Furthermore, a competition of three inhibitors (gallic acid, 4- methylumbelliferone, and scopoletin) was performed by taking help of the STD NMR experiments. Interestingly, none of them was competing for the some particular binding site. Nevertheless, in titration studies gallic acid was found best based on dissociation constant values. Moreover, an ethyl acetate fraction and its water suspension of the Terminalia Chebula RETZ, fruit extract was studied. Three compounds (4-hydroxycinnamic acid, Ethyl-4-hydroxycinnamate and lupeol) were seen to involve in interaction that were later recognized by 2D NMR and ESI mass techniques. Moreover, for the first time in the Federal University of São Carlos, these NMR methods for the determination of the bound conformation of any inhibitors towards AChE using NMR spectroscopy have been applied. |
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Repositório Institucional da UFSCAR |
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Urooj, NazishFerreira, Antonio Gilbertohttp://lattes.cnpq.br/3676462220401452http://lattes.cnpq.br/37553366205111572019-02-04T13:19:54Z2019-02-04T13:19:54Z2015-05-21UROOJ, Nazish. The implementation of NMR techniques for measuring interactions between small organic molecules/inhibitors and enzyme Acetylcholinesterase: a step towards Alzheimer´s control. 2015. Tese (Doutorado em Química) – Universidade Federal de São Carlos, São Carlos, 2015. Disponível em: https://repositorio.ufscar.br/handle/ufscar/10896.https://repositorio.ufscar.br/handle/ufscar/10896The inhibition of the acetylcholinesterase (AChE) might be an excellent therapy in controlling Alzheimer’s disease as stated by the cholinergic hypothesis. In this context, the inhibitors of AChE, are of medical and commercial paramount interest as therapeutics for Alzheimer’s disease and as pesticides. However, the conformational changes in inhibitors with AChE complex facilitate the rational design of some novel inhibitors with increased potency and specificity. Therefore, solution state NMR is a novel approach that seems to fulfil almost all conditions necessary to investigate the AChE-inhibitor complex. In this perspective, a combined strategy of STD, Tr-NOESY, DOSY, and docking simulations were applied to compare the bindings of four synthetic coumarin derivatives to tacrine for their binding potentials. Intriguingly, one of them (compound 1) was found to have not only the stronger affinity than the control but could bind with three sites. Furthermore, a competition of three inhibitors (gallic acid, 4- methylumbelliferone, and scopoletin) was performed by taking help of the STD NMR experiments. Interestingly, none of them was competing for the some particular binding site. Nevertheless, in titration studies gallic acid was found best based on dissociation constant values. Moreover, an ethyl acetate fraction and its water suspension of the Terminalia Chebula RETZ, fruit extract was studied. Three compounds (4-hydroxycinnamic acid, Ethyl-4-hydroxycinnamate and lupeol) were seen to involve in interaction that were later recognized by 2D NMR and ESI mass techniques. Moreover, for the first time in the Federal University of São Carlos, these NMR methods for the determination of the bound conformation of any inhibitors towards AChE using NMR spectroscopy have been applied.A inibição da acetilcolinesterase (AChE) pode representar um caminho para o controle da doença de Alzheimer se consideramos a hipótese colinérgica. Neste contexto, os inibidores de AChE, representam interesse tanto para a área médica como comercial utilizando-os como agentes terapêuticos para a doença de Alzheimer e como pesticidas. O entendimento das mudanças conformacionais envolvidas no complexo com os inibidores de AChE pode facilitar o planejamento racional de novos compostos, procurando aqueles com maior potencial terapêutico e melhor especificidade. Portanto, a RMN em solução é uma ferramenta muito útil para se investigar possíveis inibidores da AChE. Para tanto, uma estratégia combinando as técnicas de STD, Tr-NOESY, DOSY, e simulações computacionais foram utilizadas para comparar as interações de quatro derivados sintéticos de cumarina com o composto tacrine, utilizado como controle. Curiosamente, para um dos compostos (composta 1) foi encontrada uma maior afinidade que o próprio controle, além dele interagir em três regiões distintas. Além disso, foi realizado um experimento de competição de três inibidores (ácido gálico, 4- metilumbeliferona e escopoletina) ao mesmo tempo, através dos experimentos de STD, sendo que nenhum deles mostrou competição para uma região específica da AChE. No entanto, estudos de titulação via RMN mostrou que o ácido gálico foi o que apresentou melhor resultado baseado nos valores das constantes de dissociação medidas por RMN. Além disso, também se avaliou uma fração do extrato bruto de acetato de etila e da sua suspensão em água, oriundas dos extratos dos frutos da espécie Terminalia chebula RETZ. Três compostos (4-hidroxicinâmico, Etil-4-hidroxicinamato e lupeol) apresentaram interação com a AChE e as suas estruturas foram caracterizadas por RMN 2D e espectrometria de massas. Este trabalho representou o primeiro estudo, na UFSCar, onde se avaliou interações de possíveis inibidores da AChE utilizando técnicas de RMN.Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)engUniversidade Federal de São CarlosCâmpus São CarlosPrograma de Pós-Graduação em Química - PPGQUFSCarRessonância magnética nuclearAlzheimer, Doença deNuclear magnetic resonanceAlzheimer's diseaseCIENCIAS EXATAS E DA TERRA::QUIMICA::QUIMICA ORGANICAThe implementation of NMR techniques for measuring interactions between small organic molecules/inhibitors and enzyme Acetylcholinesterase: a step towards Alzheimer´s controlImplementação de técnicas de RMN para medir interações entre moléculas orgânicas inibidoras da enzima Acetilcolinesterase: um passo para o estudo do Alzheimerinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/doctoralThesisOnlineinfo:eu-repo/semantics/openAccessreponame:Repositório Institucional da UFSCARinstname:Universidade Federal de São Carlos (UFSCAR)instacron:UFSCARORIGINALTeseNU.pdfTeseNU.pdfapplication/pdf6463897https://{{ getenv "DSPACE_HOST" "repositorio.ufscar.br" }}/bitstream/ufscar/10896/1/TeseNU.pdf594e8fe4f3b5a42dc2c37655e57346a0MD51LICENSElicense.txtlicense.txttext/plain; charset=utf-81957https://{{ getenv "DSPACE_HOST" "repositorio.ufscar.br" }}/bitstream/ufscar/10896/2/license.txtae0398b6f8b235e40ad82cba6c50031dMD52TEXTTeseNU.pdf.txtTeseNU.pdf.txtExtracted texttext/plain269085https://{{ getenv "DSPACE_HOST" "repositorio.ufscar.br" }}/bitstream/ufscar/10896/3/TeseNU.pdf.txte12d2013c3c0d5e4bf0d5afe3eb30c6dMD53THUMBNAILTeseNU.pdf.jpgTeseNU.pdf.jpgIM Thumbnailimage/jpeg9533https://{{ getenv "DSPACE_HOST" "repositorio.ufscar.br" }}/bitstream/ufscar/10896/4/TeseNU.pdf.jpg7bd9e7de1dadaf8eb8c83a9c1732ce25MD54ufscar/108962019-09-11 03:37:13.235oai:repositorio.ufscar.br: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Repositório InstitucionalPUBhttps://repositorio.ufscar.br/oai/requestopendoar:43222023-05-25T12:57:00.609892Repositório Institucional da UFSCAR - Universidade Federal de São Carlos (UFSCAR)false |
dc.title.eng.fl_str_mv |
The implementation of NMR techniques for measuring interactions between small organic molecules/inhibitors and enzyme Acetylcholinesterase: a step towards Alzheimer´s control |
dc.title.alternative.por.fl_str_mv |
Implementação de técnicas de RMN para medir interações entre moléculas orgânicas inibidoras da enzima Acetilcolinesterase: um passo para o estudo do Alzheimer |
title |
The implementation of NMR techniques for measuring interactions between small organic molecules/inhibitors and enzyme Acetylcholinesterase: a step towards Alzheimer´s control |
spellingShingle |
The implementation of NMR techniques for measuring interactions between small organic molecules/inhibitors and enzyme Acetylcholinesterase: a step towards Alzheimer´s control Urooj, Nazish Ressonância magnética nuclear Alzheimer, Doença de Nuclear magnetic resonance Alzheimer's disease CIENCIAS EXATAS E DA TERRA::QUIMICA::QUIMICA ORGANICA |
title_short |
The implementation of NMR techniques for measuring interactions between small organic molecules/inhibitors and enzyme Acetylcholinesterase: a step towards Alzheimer´s control |
title_full |
The implementation of NMR techniques for measuring interactions between small organic molecules/inhibitors and enzyme Acetylcholinesterase: a step towards Alzheimer´s control |
title_fullStr |
The implementation of NMR techniques for measuring interactions between small organic molecules/inhibitors and enzyme Acetylcholinesterase: a step towards Alzheimer´s control |
title_full_unstemmed |
The implementation of NMR techniques for measuring interactions between small organic molecules/inhibitors and enzyme Acetylcholinesterase: a step towards Alzheimer´s control |
title_sort |
The implementation of NMR techniques for measuring interactions between small organic molecules/inhibitors and enzyme Acetylcholinesterase: a step towards Alzheimer´s control |
author |
Urooj, Nazish |
author_facet |
Urooj, Nazish |
author_role |
author |
dc.contributor.authorlattes.por.fl_str_mv |
http://lattes.cnpq.br/3755336620511157 |
dc.contributor.author.fl_str_mv |
Urooj, Nazish |
dc.contributor.advisor1.fl_str_mv |
Ferreira, Antonio Gilberto |
dc.contributor.advisor1Lattes.fl_str_mv |
http://lattes.cnpq.br/3676462220401452 |
contributor_str_mv |
Ferreira, Antonio Gilberto |
dc.subject.por.fl_str_mv |
Ressonância magnética nuclear Alzheimer, Doença de |
topic |
Ressonância magnética nuclear Alzheimer, Doença de Nuclear magnetic resonance Alzheimer's disease CIENCIAS EXATAS E DA TERRA::QUIMICA::QUIMICA ORGANICA |
dc.subject.eng.fl_str_mv |
Nuclear magnetic resonance Alzheimer's disease |
dc.subject.cnpq.fl_str_mv |
CIENCIAS EXATAS E DA TERRA::QUIMICA::QUIMICA ORGANICA |
description |
The inhibition of the acetylcholinesterase (AChE) might be an excellent therapy in controlling Alzheimer’s disease as stated by the cholinergic hypothesis. In this context, the inhibitors of AChE, are of medical and commercial paramount interest as therapeutics for Alzheimer’s disease and as pesticides. However, the conformational changes in inhibitors with AChE complex facilitate the rational design of some novel inhibitors with increased potency and specificity. Therefore, solution state NMR is a novel approach that seems to fulfil almost all conditions necessary to investigate the AChE-inhibitor complex. In this perspective, a combined strategy of STD, Tr-NOESY, DOSY, and docking simulations were applied to compare the bindings of four synthetic coumarin derivatives to tacrine for their binding potentials. Intriguingly, one of them (compound 1) was found to have not only the stronger affinity than the control but could bind with three sites. Furthermore, a competition of three inhibitors (gallic acid, 4- methylumbelliferone, and scopoletin) was performed by taking help of the STD NMR experiments. Interestingly, none of them was competing for the some particular binding site. Nevertheless, in titration studies gallic acid was found best based on dissociation constant values. Moreover, an ethyl acetate fraction and its water suspension of the Terminalia Chebula RETZ, fruit extract was studied. Three compounds (4-hydroxycinnamic acid, Ethyl-4-hydroxycinnamate and lupeol) were seen to involve in interaction that were later recognized by 2D NMR and ESI mass techniques. Moreover, for the first time in the Federal University of São Carlos, these NMR methods for the determination of the bound conformation of any inhibitors towards AChE using NMR spectroscopy have been applied. |
publishDate |
2015 |
dc.date.issued.fl_str_mv |
2015-05-21 |
dc.date.accessioned.fl_str_mv |
2019-02-04T13:19:54Z |
dc.date.available.fl_str_mv |
2019-02-04T13:19:54Z |
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 |
UROOJ, Nazish. The implementation of NMR techniques for measuring interactions between small organic molecules/inhibitors and enzyme Acetylcholinesterase: a step towards Alzheimer´s control. 2015. Tese (Doutorado em Química) – Universidade Federal de São Carlos, São Carlos, 2015. Disponível em: https://repositorio.ufscar.br/handle/ufscar/10896. |
dc.identifier.uri.fl_str_mv |
https://repositorio.ufscar.br/handle/ufscar/10896 |
identifier_str_mv |
UROOJ, Nazish. The implementation of NMR techniques for measuring interactions between small organic molecules/inhibitors and enzyme Acetylcholinesterase: a step towards Alzheimer´s control. 2015. Tese (Doutorado em Química) – Universidade Federal de São Carlos, São Carlos, 2015. Disponível em: https://repositorio.ufscar.br/handle/ufscar/10896. |
url |
https://repositorio.ufscar.br/handle/ufscar/10896 |
dc.language.iso.fl_str_mv |
eng |
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eng |
dc.rights.driver.fl_str_mv |
info:eu-repo/semantics/openAccess |
eu_rights_str_mv |
openAccess |
dc.publisher.none.fl_str_mv |
Universidade Federal de São Carlos Câmpus São Carlos |
dc.publisher.program.fl_str_mv |
Programa de Pós-Graduação em Química - PPGQ |
dc.publisher.initials.fl_str_mv |
UFSCar |
publisher.none.fl_str_mv |
Universidade Federal de São Carlos Câmpus São Carlos |
dc.source.none.fl_str_mv |
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UFSCAR |
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UFSCAR |
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Repositório Institucional da UFSCAR |
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