Estudo in silico da interação entre as enzimas Purina Nucleosídeo Fosforilase e Enoil Redutase do P. falciparum com artemisinina, beta bisaboleno e beta cariofileno
Autor(a) principal: | |
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Data de Publicação: | 2021 |
Tipo de documento: | Tese |
Idioma: | por |
Título da fonte: | Manancial - Repositório Digital da UFSM |
Texto Completo: | http://repositorio.ufsm.br/handle/1/28765 |
Resumo: | Every year millions of people die around the world due to viral, bacterial and parasitic infections. Malaria is the fifth leading cause of death for infectious diseases in the world, after respiratory infections, HIV / AIDS, diarrheal diseases and tuberculosis, with the number of victims 3 times higher than the number of victims of current armed conflicts. Malaria is also known as impaludism, terçã fever, quartã fever, maleita and others. It is caused by parasites of the genus Plasmodium, family Plasmodidae, filo Apicomplexa, with about 156 species that infect several vertebrates, and five of them can infect humans: P. falciparum, P. malarie, P. Vivax, P. Knowlesi and P. Ovale, and malaria caused by P. falciparum is the most severe form of the disease. The increasing resistance of the parasite to antimalarial chemotherapy has worried the medical community and intensified the search for new antimalarial drugs. The purine nucleoside phosphorylase enzyme (PfPNP) catalyzes the formation of hypoxanthine, essential for the purine synthesis pathway. The enzyme enoyl reductase (PfENR), has significant importance in regulating the fatty acid elongation cycle. Beta Cariophilene and Beta Bisabolene are sesquiterpenes found in various plants such as cinnamon (Cinnamomum spp.), Black pepper (Piper nigrum L.), clove (Syzygium aromaticum), cannabis (Cannabis sativa L.) lavender (Lavandula angustifolia), oregano (Origanum vulgare L.), rosemary (Rosmarinus officinalis) Copaíba (copaífera reticulata), and exhibit anti-inflammatory, anticarcinogenic, antimicrobial, antioxidative and analgesic therapeutic properties. In this work, three-dimensional models for the enzymes were constructed from structures obtained in the Protein Data Bank database using Modeller 9.23 software and Verify3D, MolProbity and ModFold validation techniques were used to determine the stereochemical quality of the models. The Molecular Dynamics (DM) of the enzymes and the topology of the ligands were performed using the GROMACS 5.1.4 software package, with the Gromos 96.1 force field (53A6) Calculations of Root Mean Square Deviation (RMSD), Root Mean Square Fluctuation (RMSF) and radius of gyration (Rg) were used for comparison and analysis of the systems with binders in relation to the free form. The binding sites of the enzymes with the ligands were obtained with Autodock Vina 1.1.2 and Autodock Tools 1.5.6 molecular docking software. Molecular docking simulations were also carried out with Artemisinin, which is the most recently used treatment for malaria, and with triclosan for PfEACPR, as this is a known inhibitor of this enzyme and with inosine, which is a natural inhibitor of the enzyme PfPNP. |
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Estudo in silico da interação entre as enzimas Purina Nucleosídeo Fosforilase e Enoil Redutase do P. falciparum com artemisinina, beta bisaboleno e beta cariofilenoIn silico study of the interaction between the Purine Nucleoside Phosphorylase and Enoy Reductase enzymes of P. falciparum with beta-bisolol and beta-caryophyllenePlasmodium falciparumMaláriaEnoil RedutasePurina Nucleosídeo FosforilaseSesquiterpenosMalariaEnoyl ReductasePurine Nucleoside PhosphorylaseSesquiterpenesCNPQ::CIENCIAS EXATAS E DA TERRA::FISICAEvery year millions of people die around the world due to viral, bacterial and parasitic infections. Malaria is the fifth leading cause of death for infectious diseases in the world, after respiratory infections, HIV / AIDS, diarrheal diseases and tuberculosis, with the number of victims 3 times higher than the number of victims of current armed conflicts. Malaria is also known as impaludism, terçã fever, quartã fever, maleita and others. It is caused by parasites of the genus Plasmodium, family Plasmodidae, filo Apicomplexa, with about 156 species that infect several vertebrates, and five of them can infect humans: P. falciparum, P. malarie, P. Vivax, P. Knowlesi and P. Ovale, and malaria caused by P. falciparum is the most severe form of the disease. The increasing resistance of the parasite to antimalarial chemotherapy has worried the medical community and intensified the search for new antimalarial drugs. The purine nucleoside phosphorylase enzyme (PfPNP) catalyzes the formation of hypoxanthine, essential for the purine synthesis pathway. The enzyme enoyl reductase (PfENR), has significant importance in regulating the fatty acid elongation cycle. Beta Cariophilene and Beta Bisabolene are sesquiterpenes found in various plants such as cinnamon (Cinnamomum spp.), Black pepper (Piper nigrum L.), clove (Syzygium aromaticum), cannabis (Cannabis sativa L.) lavender (Lavandula angustifolia), oregano (Origanum vulgare L.), rosemary (Rosmarinus officinalis) Copaíba (copaífera reticulata), and exhibit anti-inflammatory, anticarcinogenic, antimicrobial, antioxidative and analgesic therapeutic properties. In this work, three-dimensional models for the enzymes were constructed from structures obtained in the Protein Data Bank database using Modeller 9.23 software and Verify3D, MolProbity and ModFold validation techniques were used to determine the stereochemical quality of the models. The Molecular Dynamics (DM) of the enzymes and the topology of the ligands were performed using the GROMACS 5.1.4 software package, with the Gromos 96.1 force field (53A6) Calculations of Root Mean Square Deviation (RMSD), Root Mean Square Fluctuation (RMSF) and radius of gyration (Rg) were used for comparison and analysis of the systems with binders in relation to the free form. The binding sites of the enzymes with the ligands were obtained with Autodock Vina 1.1.2 and Autodock Tools 1.5.6 molecular docking software. Molecular docking simulations were also carried out with Artemisinin, which is the most recently used treatment for malaria, and with triclosan for PfEACPR, as this is a known inhibitor of this enzyme and with inosine, which is a natural inhibitor of the enzyme PfPNP.Todos os anos milhões de pessoas morrem ao redor do mundo devido a infecções virais, bacterianas e parasitárias. A malária é a quinta causa de morte por doenças infecciosas no mundo, depois de infecções respiratórias, HIV/AIDS, doenças diarreicas e tuberculose, com o número de vítimas 3 vezes maior que o número de vítimas por conflitos armados da atualidade. A malária é também conhecida como impaludismo, febre terçã, febre quartã, maleita e outros, é causada por parasitas do gênero Plasmodium, família Plasmodidae, filo Apicomplexa, havendo cerca de 156 espécies que infectam vários vertebrados, e cinco delas podem infectar humanos: P. falciparum, P. malarie, P. Vivax, P. Knowlesi e P. Ovale, sendo a malária causada pelo P. falciparum é a forma mais grave da doença. A resistência crescente do parasita em relação a quimioterapia antimalárica tem preocupado a comunidade médica e intensificado a busca por novos medicamentos antimaláricos. As enzimas Purina Nucleosídeo Fosforilase (PfPNP) e Enoil Redutase (Enoyl Acil Carrier Protein Reductase) (PfEACPR) do P. falciparum são potenciais alvos para eliminação do parasita. A primeira catalisa a formação de hipoxantina, essencial para a via de síntese de purinas, enquanto a segunda possui importância significativa na regulação do ciclo de elongamento de ácidos graxos. O Beta Cariofileno e o Beta Bisaboleno são sesquiterpenos encontrados em diversas plantas como canela (Cinnamomum spp.), Pimenta preta (Piper nigrum L.), cravo (Syzygium aromaticum), cannabis (Cannabis sativa L.) lavanda (Lavandula angustifolia), orégano (Origanum vulgare L.), alecrim (Rosmarinus officinalis) Copaíba (copaífera reticulata), e apresentam propriedades terapêuticas anti-inflamatórias , anticarcinógenicas , antimicrobianas , antioxidativas e atividades analgésicas. Neste trabalho, foram construídos modelos tridimensionais para as enzimas a partir de estruturas obtidas no banco de dados Protein Data Bank, utilizando o software Modeller 9.23 e foram utilizadas as técnicas de validação Verify3D, Procheck e ModFold para determinar a qualidade estereoquímica dos modelos. As Dinâmicas Moleculares (DM) das enzimas e a topologia dos ligantes foram realizadas utilizando o pacote de software GROMACS 2020, sob CNTP. Os cálculos de desvio médio quadrático (RMSD), Raiz quadrada da flutuação quadrática média (RMSF) e raio de giro (Rg) foram utilizados para comparação e análise dos sistemas com ligantes em relação a forma livre. Os sítios de ligação das enzimas e a interação com os ligantes foram obtidos com os softwares de docagem molecular Autodock Vina 1.1.2 e Autodock Tools 1.5.6. Foram também realizadas simulações de docking molecular com a Artemisinina, que é o tratamento mais utilizado recentemente para a malária, e com o triclosan para a PfEACPR, pois este é um inibidor conhecido desta enzima e com a inosina, que é um inibidor natural da enzima PfPNP. Os modelos construídos para as enzimas apresentaram boa qualidade estereoquímica e na estrutura 3D de acordo com as técnicas de validação empregadas. A estrutura da enzima PfEACPR apresentou boa estabilidade e compactação, mostradas pelos resultados da Dinâmica Molecular, já para a enzima PfPNP não foi possivel observar estabilidade pois o tempo de simulação para a mesma foi insuficiente. Nos resultados de Docking Molecular pudemos observar que os ligantes Beta bisaboleno interagem em regiões muito próximas entre si e da Artemisinina, através de interações hidrofóbicas nas duas enzimas.Universidade Federal de Santa MariaBrasilFísicaUFSMPrograma de Pós-Graduação em FísicaCentro de Ciências Naturais e ExatasPiquini, Paulo Cesarhttp://lattes.cnpq.br/4496249071363237Machado, Karina dos SantosAlmeida, James Moraes deMombach, José Carlos MerinoRocha, João Batista Teixeira daNagata, Khayth Marronny Rabelo2023-04-19T18:32:05Z2023-04-19T18:32:05Z2021-08-31info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/doctoralThesisapplication/pdfhttp://repositorio.ufsm.br/handle/1/28765porAttribution-NonCommercial-NoDerivatives 4.0 Internationalhttp://creativecommons.org/licenses/by-nc-nd/4.0/info:eu-repo/semantics/openAccessreponame:Manancial - Repositório Digital da UFSMinstname:Universidade Federal de Santa Maria (UFSM)instacron:UFSM2023-04-19T18:32:05Zoai:repositorio.ufsm.br:1/28765Biblioteca Digital de Teses e Dissertaçõeshttps://repositorio.ufsm.br/ONGhttps://repositorio.ufsm.br/oai/requestatendimento.sib@ufsm.br||tedebc@gmail.comopendoar:2023-04-19T18:32:05Manancial - Repositório Digital da UFSM - Universidade Federal de Santa Maria (UFSM)false |
dc.title.none.fl_str_mv |
Estudo in silico da interação entre as enzimas Purina Nucleosídeo Fosforilase e Enoil Redutase do P. falciparum com artemisinina, beta bisaboleno e beta cariofileno In silico study of the interaction between the Purine Nucleoside Phosphorylase and Enoy Reductase enzymes of P. falciparum with beta-bisolol and beta-caryophyllene |
title |
Estudo in silico da interação entre as enzimas Purina Nucleosídeo Fosforilase e Enoil Redutase do P. falciparum com artemisinina, beta bisaboleno e beta cariofileno |
spellingShingle |
Estudo in silico da interação entre as enzimas Purina Nucleosídeo Fosforilase e Enoil Redutase do P. falciparum com artemisinina, beta bisaboleno e beta cariofileno Nagata, Khayth Marronny Rabelo Plasmodium falciparum Malária Enoil Redutase Purina Nucleosídeo Fosforilase Sesquiterpenos Malaria Enoyl Reductase Purine Nucleoside Phosphorylase Sesquiterpenes CNPQ::CIENCIAS EXATAS E DA TERRA::FISICA |
title_short |
Estudo in silico da interação entre as enzimas Purina Nucleosídeo Fosforilase e Enoil Redutase do P. falciparum com artemisinina, beta bisaboleno e beta cariofileno |
title_full |
Estudo in silico da interação entre as enzimas Purina Nucleosídeo Fosforilase e Enoil Redutase do P. falciparum com artemisinina, beta bisaboleno e beta cariofileno |
title_fullStr |
Estudo in silico da interação entre as enzimas Purina Nucleosídeo Fosforilase e Enoil Redutase do P. falciparum com artemisinina, beta bisaboleno e beta cariofileno |
title_full_unstemmed |
Estudo in silico da interação entre as enzimas Purina Nucleosídeo Fosforilase e Enoil Redutase do P. falciparum com artemisinina, beta bisaboleno e beta cariofileno |
title_sort |
Estudo in silico da interação entre as enzimas Purina Nucleosídeo Fosforilase e Enoil Redutase do P. falciparum com artemisinina, beta bisaboleno e beta cariofileno |
author |
Nagata, Khayth Marronny Rabelo |
author_facet |
Nagata, Khayth Marronny Rabelo |
author_role |
author |
dc.contributor.none.fl_str_mv |
Piquini, Paulo Cesar http://lattes.cnpq.br/4496249071363237 Machado, Karina dos Santos Almeida, James Moraes de Mombach, José Carlos Merino Rocha, João Batista Teixeira da |
dc.contributor.author.fl_str_mv |
Nagata, Khayth Marronny Rabelo |
dc.subject.por.fl_str_mv |
Plasmodium falciparum Malária Enoil Redutase Purina Nucleosídeo Fosforilase Sesquiterpenos Malaria Enoyl Reductase Purine Nucleoside Phosphorylase Sesquiterpenes CNPQ::CIENCIAS EXATAS E DA TERRA::FISICA |
topic |
Plasmodium falciparum Malária Enoil Redutase Purina Nucleosídeo Fosforilase Sesquiterpenos Malaria Enoyl Reductase Purine Nucleoside Phosphorylase Sesquiterpenes CNPQ::CIENCIAS EXATAS E DA TERRA::FISICA |
description |
Every year millions of people die around the world due to viral, bacterial and parasitic infections. Malaria is the fifth leading cause of death for infectious diseases in the world, after respiratory infections, HIV / AIDS, diarrheal diseases and tuberculosis, with the number of victims 3 times higher than the number of victims of current armed conflicts. Malaria is also known as impaludism, terçã fever, quartã fever, maleita and others. It is caused by parasites of the genus Plasmodium, family Plasmodidae, filo Apicomplexa, with about 156 species that infect several vertebrates, and five of them can infect humans: P. falciparum, P. malarie, P. Vivax, P. Knowlesi and P. Ovale, and malaria caused by P. falciparum is the most severe form of the disease. The increasing resistance of the parasite to antimalarial chemotherapy has worried the medical community and intensified the search for new antimalarial drugs. The purine nucleoside phosphorylase enzyme (PfPNP) catalyzes the formation of hypoxanthine, essential for the purine synthesis pathway. The enzyme enoyl reductase (PfENR), has significant importance in regulating the fatty acid elongation cycle. Beta Cariophilene and Beta Bisabolene are sesquiterpenes found in various plants such as cinnamon (Cinnamomum spp.), Black pepper (Piper nigrum L.), clove (Syzygium aromaticum), cannabis (Cannabis sativa L.) lavender (Lavandula angustifolia), oregano (Origanum vulgare L.), rosemary (Rosmarinus officinalis) Copaíba (copaífera reticulata), and exhibit anti-inflammatory, anticarcinogenic, antimicrobial, antioxidative and analgesic therapeutic properties. In this work, three-dimensional models for the enzymes were constructed from structures obtained in the Protein Data Bank database using Modeller 9.23 software and Verify3D, MolProbity and ModFold validation techniques were used to determine the stereochemical quality of the models. The Molecular Dynamics (DM) of the enzymes and the topology of the ligands were performed using the GROMACS 5.1.4 software package, with the Gromos 96.1 force field (53A6) Calculations of Root Mean Square Deviation (RMSD), Root Mean Square Fluctuation (RMSF) and radius of gyration (Rg) were used for comparison and analysis of the systems with binders in relation to the free form. The binding sites of the enzymes with the ligands were obtained with Autodock Vina 1.1.2 and Autodock Tools 1.5.6 molecular docking software. Molecular docking simulations were also carried out with Artemisinin, which is the most recently used treatment for malaria, and with triclosan for PfEACPR, as this is a known inhibitor of this enzyme and with inosine, which is a natural inhibitor of the enzyme PfPNP. |
publishDate |
2021 |
dc.date.none.fl_str_mv |
2021-08-31 2023-04-19T18:32:05Z 2023-04-19T18:32:05Z |
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.uri.fl_str_mv |
http://repositorio.ufsm.br/handle/1/28765 |
url |
http://repositorio.ufsm.br/handle/1/28765 |
dc.language.iso.fl_str_mv |
por |
language |
por |
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.format.none.fl_str_mv |
application/pdf |
dc.publisher.none.fl_str_mv |
Universidade Federal de Santa Maria Brasil Física UFSM Programa de Pós-Graduação em Física Centro de Ciências Naturais e Exatas |
publisher.none.fl_str_mv |
Universidade Federal de Santa Maria Brasil Física UFSM Programa de Pós-Graduação em Física Centro de Ciências Naturais e Exatas |
dc.source.none.fl_str_mv |
reponame:Manancial - Repositório Digital da UFSM instname:Universidade Federal de Santa Maria (UFSM) instacron:UFSM |
instname_str |
Universidade Federal de Santa Maria (UFSM) |
instacron_str |
UFSM |
institution |
UFSM |
reponame_str |
Manancial - Repositório Digital da UFSM |
collection |
Manancial - Repositório Digital da UFSM |
repository.name.fl_str_mv |
Manancial - Repositório Digital da UFSM - Universidade Federal de Santa Maria (UFSM) |
repository.mail.fl_str_mv |
atendimento.sib@ufsm.br||tedebc@gmail.com |
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1805922073090981888 |