Estudos in silico aplicados a compostos orgânicos de mercúrio e selênio em sistemas biológicos
Ano de defesa: | 2020 |
---|---|
Autor(a) principal: | |
Orientador(a): | |
Banca de defesa: | , , , |
Tipo de documento: | Tese |
Tipo de acesso: | Acesso aberto |
Idioma: | por |
Instituição de defesa: |
Universidade Federal de Santa Maria
Centro de Ciências Naturais e Exatas |
Programa de Pós-Graduação: |
Programa de Pós-Graduação em Ciências Biológicas: Bioquímica Toxicológica
|
Departamento: |
Bioquímica
|
País: |
Brasil
|
Palavras-chave em Português: | |
Palavras-chave em Inglês: | |
Área do conhecimento CNPq: | |
Link de acesso: | http://repositorio.ufsm.br/handle/1/22033 |
Resumo: | Methylmercury (MeHg) is a potent neurotoxin, which is associated with the inhibition of Glutathione Peroxidase (GPx) and Thioredoxin Reductase (TrxR) selenozymes, however, the mechanism of MeHg inhibition, at the molecular level, need to be elucidated. Organic selenium compounds, such as Ebselen (Ebs) and diphenyl diselenide (DPDSe), have shown promising results against MeHg toxicity. On the other hand, organoselenium compounds can also be considered toxic, since they are able to oxidize the thiol groups from the mammalian δ-aminolevulinic acid dehydratase (δ-AlaD). The use of in silico tools, such as molecular docking, homology modeling, and DFT calculations are important because they allow analysis at the molecular level. In addition, new synthetic molecules can be designed and virtually tested. Thus, the present work aims to understand, at the molecular level, the chemical interactions involved between organoselenium and MeHg molecules with their biological targets, as well as, to propose new and more effective compounds. The results of molecular docking with GPx and TrxR demonstrated that MeHg is capable of interacting in its active sites, where a nucleophilic attack from selenocysteine residue (Sec), could lead to the formation of the Sec-SeHgMe adduct, inhibiting the enzymes. DFT calculations suggest that Sec-SeHgMe could undergo β-elimination, leading to the dehydroalanine (Dha). The interactions between organoselenium compounds and δ-AlaD showed that selenoxides are more reactive than their respective selenides, and they have Zn...O coordination, which could facilitate the attack of the Cys124 thiolate on the Se atom. New compounds, such as pyridinyl(quinolyl)-thio(seleno)semicarbazides and Ebs derivatives are proposed for therapeutic purposes. These data help us to understand the toxicology of MeHg and organoselenium molecules and can guide the development of new Hg chelating agents with high selectivity and with less adverse effects. |
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2021-08-23T20:18:10Z2021-08-23T20:18:10Z2020-08-10http://repositorio.ufsm.br/handle/1/22033Methylmercury (MeHg) is a potent neurotoxin, which is associated with the inhibition of Glutathione Peroxidase (GPx) and Thioredoxin Reductase (TrxR) selenozymes, however, the mechanism of MeHg inhibition, at the molecular level, need to be elucidated. Organic selenium compounds, such as Ebselen (Ebs) and diphenyl diselenide (DPDSe), have shown promising results against MeHg toxicity. On the other hand, organoselenium compounds can also be considered toxic, since they are able to oxidize the thiol groups from the mammalian δ-aminolevulinic acid dehydratase (δ-AlaD). The use of in silico tools, such as molecular docking, homology modeling, and DFT calculations are important because they allow analysis at the molecular level. In addition, new synthetic molecules can be designed and virtually tested. Thus, the present work aims to understand, at the molecular level, the chemical interactions involved between organoselenium and MeHg molecules with their biological targets, as well as, to propose new and more effective compounds. The results of molecular docking with GPx and TrxR demonstrated that MeHg is capable of interacting in its active sites, where a nucleophilic attack from selenocysteine residue (Sec), could lead to the formation of the Sec-SeHgMe adduct, inhibiting the enzymes. DFT calculations suggest that Sec-SeHgMe could undergo β-elimination, leading to the dehydroalanine (Dha). The interactions between organoselenium compounds and δ-AlaD showed that selenoxides are more reactive than their respective selenides, and they have Zn...O coordination, which could facilitate the attack of the Cys124 thiolate on the Se atom. New compounds, such as pyridinyl(quinolyl)-thio(seleno)semicarbazides and Ebs derivatives are proposed for therapeutic purposes. These data help us to understand the toxicology of MeHg and organoselenium molecules and can guide the development of new Hg chelating agents with high selectivity and with less adverse effects.O metilmercúrio (MeHg) é uma potente neurotoxina, associado à inibição das selenoenzimas Glutationa Peroxidase (GPx) e Tioredoxina Redutase (TrxR), no entanto, o mecanismo de inibição do MeHg a nível molecular ainda precisa ser elucidado. Compostos orgânicos de Se, como o Ebselen (Ebs) e o disseleneto de difenila (DPDSe), têm demonstrado resultados promissores contra o toxicidade do MeHg. Por outro lado, os organosselênios também podem ser considerados tóxicos, uma vez que oxidam os grupos tióis proteicos da enzima ácido δ-aminolevulínico desidratase de mamífero (δ-AlaD). O uso de ferramentas in silico, tais como docking molecular, modelagem por homologia, e cálculos DFT são importantes, pois permitem uma análise a nível molecular. Além disso, novos moléculas sintéticas podem ser planejadas e virtualmente testadas. Assim, o presente trabalho tem o objetivo de compreender, à nível molecular, as interações químicas envolvidas entre organosselênios e MeHg com seus alvos biológicos, bem como propor novos compostos. Os resultados de docking molecular com a GPx e TrxR demonstraram que o MeHg é capaz de interagir nos seus sítio ativos, onde um ataque nucleofilico do resíduo de selenocisteina (Sec), poderia levar a formação do aduto Sec-SeHgMe, inibindo as enzimas. Os cálculos de DFT sugerem que Sec-SeHgMe poderia sofrer uma β-eliminação, formando assim a desidroalanina (Dha). Já as interações entre organosselênios e δ-AlaD mostraram que os selenóxidos, além de mais reativos que seus respectivos selenetos, possuem uma coordenação Zn...O o que poderia facilitar o ataque do tiolato da Cys124 ao átomo de Se. Por fim, novos compostos tio(seleno)semicarbazidas e derivados do Ebs são propostos para fins terapêuticos. Esses dados auxiliam no entendimento da toxicologia do MeHg e organosselênios, e podem guiar o desenvolvimento de futuros agentes quelantes de Hg com alta seletividade e com menor efeitos adversos.Conselho Nacional de Pesquisa e Desenvolvimento Científico e Tecnológico - CNPqCoordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPESFundação de Amparo à Pesquisa do Estado do Rio Grande do Sul - FAPERGSporUniversidade Federal de Santa MariaCentro de Ciências Naturais e ExatasPrograma de Pós-Graduação em Ciências Biológicas: Bioquímica ToxicológicaUFSMBrasilBioquímicaAttribution-NonCommercial-NoDerivatives 4.0 Internationalhttp://creativecommons.org/licenses/by-nc-nd/4.0/info:eu-repo/semantics/openAccessDocagemSelenoproteínasMetilmercúrioDFTModelagem por homologiaMolecular dockingSelenoproteinsMethylmercuryHomology modelingCNPQ::CIENCIAS BIOLOGICAS::BIOQUIMICAEstudos in silico aplicados a compostos orgânicos de mercúrio e selênio em sistemas biológicosIn silico studies applied to organic compounds of mercury and selenium in biological systemsinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/doctoralThesisRocha, João Batista Teixeira dahttp://lattes.cnpq.br/3935055744673018Andricopulo, Adriano DefiniDalla Corte, Cristiane LenzMachado, Karina dos SantosRodrigues, Oscar Endrigo Dorneleshttp://lattes.cnpq.br/8323436856891273Nogara, Pablo Andrei20080000000260060060060060060060027186f63-94dd-4f0f-8181-7ce1b08350091b7f098d-470e-4587-8a7f-d6dc3b3e29cc30870eae-bf2f-4d5a-9e63-1e50276c0c79ed6a73a6-ab4c-4b6e-ac2a-ec6b5c7c040b2c96c13e-267d-4c27-ab95-52d3986d5e929dfccbe0-bd16-4e23-a1fb-8e55f871ce46reponame:Manancial - Repositório Digital da UFSMinstname:Universidade Federal de Santa Maria (UFSM)instacron:UFSMORIGINALTES_PPGCBBT_2020_NOGARA_PABLO.pdfTES_PPGCBBT_2020_NOGARA_PABLO.pdfTeseapplication/pdf30427332http://repositorio.ufsm.br/bitstream/1/22033/1/TES_PPGCBBT_2020_NOGARA_PABLO.pdf2c2b2c499b54f1c1ecb138dd8b8d1535MD51CC-LICENSElicense_rdflicense_rdfapplication/rdf+xml; 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dc.title.por.fl_str_mv |
Estudos in silico aplicados a compostos orgânicos de mercúrio e selênio em sistemas biológicos |
dc.title.alternative.eng.fl_str_mv |
In silico studies applied to organic compounds of mercury and selenium in biological systems |
title |
Estudos in silico aplicados a compostos orgânicos de mercúrio e selênio em sistemas biológicos |
spellingShingle |
Estudos in silico aplicados a compostos orgânicos de mercúrio e selênio em sistemas biológicos Nogara, Pablo Andrei Docagem Selenoproteínas Metilmercúrio DFT Modelagem por homologia Molecular docking Selenoproteins Methylmercury Homology modeling CNPQ::CIENCIAS BIOLOGICAS::BIOQUIMICA |
title_short |
Estudos in silico aplicados a compostos orgânicos de mercúrio e selênio em sistemas biológicos |
title_full |
Estudos in silico aplicados a compostos orgânicos de mercúrio e selênio em sistemas biológicos |
title_fullStr |
Estudos in silico aplicados a compostos orgânicos de mercúrio e selênio em sistemas biológicos |
title_full_unstemmed |
Estudos in silico aplicados a compostos orgânicos de mercúrio e selênio em sistemas biológicos |
title_sort |
Estudos in silico aplicados a compostos orgânicos de mercúrio e selênio em sistemas biológicos |
author |
Nogara, Pablo Andrei |
author_facet |
Nogara, Pablo Andrei |
author_role |
author |
dc.contributor.advisor1.fl_str_mv |
Rocha, João Batista Teixeira da |
dc.contributor.advisor1Lattes.fl_str_mv |
http://lattes.cnpq.br/3935055744673018 |
dc.contributor.referee1.fl_str_mv |
Andricopulo, Adriano Defini |
dc.contributor.referee2.fl_str_mv |
Dalla Corte, Cristiane Lenz |
dc.contributor.referee3.fl_str_mv |
Machado, Karina dos Santos |
dc.contributor.referee4.fl_str_mv |
Rodrigues, Oscar Endrigo Dorneles |
dc.contributor.authorLattes.fl_str_mv |
http://lattes.cnpq.br/8323436856891273 |
dc.contributor.author.fl_str_mv |
Nogara, Pablo Andrei |
contributor_str_mv |
Rocha, João Batista Teixeira da Andricopulo, Adriano Defini Dalla Corte, Cristiane Lenz Machado, Karina dos Santos Rodrigues, Oscar Endrigo Dorneles |
dc.subject.por.fl_str_mv |
Docagem Selenoproteínas Metilmercúrio DFT Modelagem por homologia |
topic |
Docagem Selenoproteínas Metilmercúrio DFT Modelagem por homologia Molecular docking Selenoproteins Methylmercury Homology modeling CNPQ::CIENCIAS BIOLOGICAS::BIOQUIMICA |
dc.subject.eng.fl_str_mv |
Molecular docking Selenoproteins Methylmercury Homology modeling |
dc.subject.cnpq.fl_str_mv |
CNPQ::CIENCIAS BIOLOGICAS::BIOQUIMICA |
description |
Methylmercury (MeHg) is a potent neurotoxin, which is associated with the inhibition of Glutathione Peroxidase (GPx) and Thioredoxin Reductase (TrxR) selenozymes, however, the mechanism of MeHg inhibition, at the molecular level, need to be elucidated. Organic selenium compounds, such as Ebselen (Ebs) and diphenyl diselenide (DPDSe), have shown promising results against MeHg toxicity. On the other hand, organoselenium compounds can also be considered toxic, since they are able to oxidize the thiol groups from the mammalian δ-aminolevulinic acid dehydratase (δ-AlaD). The use of in silico tools, such as molecular docking, homology modeling, and DFT calculations are important because they allow analysis at the molecular level. In addition, new synthetic molecules can be designed and virtually tested. Thus, the present work aims to understand, at the molecular level, the chemical interactions involved between organoselenium and MeHg molecules with their biological targets, as well as, to propose new and more effective compounds. The results of molecular docking with GPx and TrxR demonstrated that MeHg is capable of interacting in its active sites, where a nucleophilic attack from selenocysteine residue (Sec), could lead to the formation of the Sec-SeHgMe adduct, inhibiting the enzymes. DFT calculations suggest that Sec-SeHgMe could undergo β-elimination, leading to the dehydroalanine (Dha). The interactions between organoselenium compounds and δ-AlaD showed that selenoxides are more reactive than their respective selenides, and they have Zn...O coordination, which could facilitate the attack of the Cys124 thiolate on the Se atom. New compounds, such as pyridinyl(quinolyl)-thio(seleno)semicarbazides and Ebs derivatives are proposed for therapeutic purposes. These data help us to understand the toxicology of MeHg and organoselenium molecules and can guide the development of new Hg chelating agents with high selectivity and with less adverse effects. |
publishDate |
2020 |
dc.date.issued.fl_str_mv |
2020-08-10 |
dc.date.accessioned.fl_str_mv |
2021-08-23T20:18:10Z |
dc.date.available.fl_str_mv |
2021-08-23T20:18:10Z |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/doctoralThesis |
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doctoralThesis |
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publishedVersion |
dc.identifier.uri.fl_str_mv |
http://repositorio.ufsm.br/handle/1/22033 |
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http://repositorio.ufsm.br/handle/1/22033 |
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por |
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por |
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200800000002 |
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600 600 600 600 600 600 600 |
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dc.rights.driver.fl_str_mv |
Attribution-NonCommercial-NoDerivatives 4.0 International http://creativecommons.org/licenses/by-nc-nd/4.0/ info:eu-repo/semantics/openAccess |
rights_invalid_str_mv |
Attribution-NonCommercial-NoDerivatives 4.0 International http://creativecommons.org/licenses/by-nc-nd/4.0/ |
eu_rights_str_mv |
openAccess |
dc.publisher.none.fl_str_mv |
Universidade Federal de Santa Maria Centro de Ciências Naturais e Exatas |
dc.publisher.program.fl_str_mv |
Programa de Pós-Graduação em Ciências Biológicas: Bioquímica Toxicológica |
dc.publisher.initials.fl_str_mv |
UFSM |
dc.publisher.country.fl_str_mv |
Brasil |
dc.publisher.department.fl_str_mv |
Bioquímica |
publisher.none.fl_str_mv |
Universidade Federal de Santa Maria Centro de Ciências Naturais e Exatas |
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