Modelagem molecular por homologia e estudos de Docking molecular de potenciais alvos terapêuticos para Doença de Chagas
Autor(a) principal: | |
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Data de Publicação: | 2011 |
Tipo de documento: | Tese |
Idioma: | por |
Título da fonte: | Repositório Institucional da Universidade Federal Fluminense (RIUFF) |
Texto Completo: | https://app.uff.br/riuff/handle/1/20651 |
Resumo: | The development of new drugs against Trypanosoma cruzi is still needed since the only drugs used to treat cause serious side effects. Naphthoquinones derivatives β-lapachone and oxiran-alfa-lapachone have high trypanocidal activity and act on different targets in the parasite. With the aim of obtaining parameters that influence the activity profile of these derivatives, computational techniques were used to study the interaction between protease inhibitors and oligopeptidase B and cruzain. In the first part of this work models of oligopeptidase B were built by homology modeling. Due to the low identity with the template 2BKL, models were constructed from alignments performed in ClustalW and 3D-coffee while were used SWISS-MODEL and Modeller programs to obtain three-dimensional structure. After the models validation, the model obtained from SWISS-MODEL and the alignment with ClustalW yielded better results, so it was selected for use in molecular docking studies. In the second part of this work, we studied molecular docking of β- lapachone and oxiran-alfa-lapachone in the active site of cruzain and oligopeptidase B. Studies of molecular docking in the active site of cruzain showed that β-lapachone, E64, a standard cysteine protease inhibitor, are involved in hydrogen bonds and interact hydrophobically with residues of the S1 sub-site, important for the specificity of the enzyme, justifying the inhibitory activity, while the oxiran-alfa lapachone does not participate in important interactions. The results of molecular docking in the active site of oligopeptidase B indicated that the oxiran-alfa-lapachone is located near the catalytic triad of the enzyme. The analysis of the complex showed that it participates in two hydrogen bonds with residues ARG649 and TYR481 corroborate the trypanocidal activity, and guide the oxiran ring with the SER562 the catalytic triad, indicating a possible nucleophilic attack (irreversible inhibition). The oligopeptidase B enzymes do not have homologues in humans, therefore is a potential target in studies of new drugs with trypanocidal activity. Thus, based on tests carried out and jointly with data obtained from the literature of oligopeptidase B inhibitors, 8 new derivatives of oxiran-alfa-lapachone were proposed based on molecular hybridization in order to increase the surface contact with the active site through hydrophobic interactions and salt bridges, as described in the literature as important for the inhibition of serine proteases. |
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Modelagem molecular por homologia e estudos de Docking molecular de potenciais alvos terapêuticos para Doença de ChagasHomology molecular modeling and molecular docking studies of potential therapeutic targets for Chagas DiseaseNaftoquinonaModelo molecularDoença de ChagasNaphthoquinoneMolecular modelChagas DiseaseCNPQ::CIENCIAS EXATAS E DA TERRA::QUIMICAThe development of new drugs against Trypanosoma cruzi is still needed since the only drugs used to treat cause serious side effects. Naphthoquinones derivatives β-lapachone and oxiran-alfa-lapachone have high trypanocidal activity and act on different targets in the parasite. With the aim of obtaining parameters that influence the activity profile of these derivatives, computational techniques were used to study the interaction between protease inhibitors and oligopeptidase B and cruzain. In the first part of this work models of oligopeptidase B were built by homology modeling. Due to the low identity with the template 2BKL, models were constructed from alignments performed in ClustalW and 3D-coffee while were used SWISS-MODEL and Modeller programs to obtain three-dimensional structure. After the models validation, the model obtained from SWISS-MODEL and the alignment with ClustalW yielded better results, so it was selected for use in molecular docking studies. In the second part of this work, we studied molecular docking of β- lapachone and oxiran-alfa-lapachone in the active site of cruzain and oligopeptidase B. Studies of molecular docking in the active site of cruzain showed that β-lapachone, E64, a standard cysteine protease inhibitor, are involved in hydrogen bonds and interact hydrophobically with residues of the S1 sub-site, important for the specificity of the enzyme, justifying the inhibitory activity, while the oxiran-alfa lapachone does not participate in important interactions. The results of molecular docking in the active site of oligopeptidase B indicated that the oxiran-alfa-lapachone is located near the catalytic triad of the enzyme. The analysis of the complex showed that it participates in two hydrogen bonds with residues ARG649 and TYR481 corroborate the trypanocidal activity, and guide the oxiran ring with the SER562 the catalytic triad, indicating a possible nucleophilic attack (irreversible inhibition). The oligopeptidase B enzymes do not have homologues in humans, therefore is a potential target in studies of new drugs with trypanocidal activity. Thus, based on tests carried out and jointly with data obtained from the literature of oligopeptidase B inhibitors, 8 new derivatives of oxiran-alfa-lapachone were proposed based on molecular hybridization in order to increase the surface contact with the active site through hydrophobic interactions and salt bridges, as described in the literature as important for the inhibition of serine proteases.Coordenação de Aperfeiçoamento de Pessoal de Nível SuperiorO desenvolvimento de novos fármacos contra o Trypanosoma cruzi ainda é necessário uma vez que os únicos fármacos usados no tratamento causam efeitos colaterais graves. Os derivados naftoquinônicos β-lapachona e oxirano-alfa-lapachona possuem alta atividade tripanocida e atuam em diferentes alvos no parasita. Com o objetivo de se obter parâmetros que influenciam no perfil da atividade desses derivados, foram utilizadas técnicas computacionais para o estudo da interação entre os inibidores e as proteases cruzaína e oligopeptidase B do parasita. Na primeira parte deste trabalho construímos modelos por homologia da oligopeptidase B. Devido à baixa identidade com o molde 2BKL, foram construídos modelos a partir de alinhamentos realizados no ClustalW e no 3Dcoffee, enquanto foram utilizados os programas SWISS-MODEL e Modeller para obtenção da estrutura tridimensional. Após a validação dos modelos, aquele obtido no SWISS-MODEL a partir do alinhamento com ClustalW apresentou melhores resultados, assim foi selecionado para o uso no estudo de docking molecular. Na segunda parte desse trabalho foram realizados estudos de docking molecular da β-lapachona e do oxirano-alfa-lapachona no sítio ativo da cruzaína e da oligopeptidase B. Os estudos de docking molecular no sítio ativo da cruzaína mostraram que β-lapachona e E64, um inibidor padrão de cisteinoprotease, participam de ligações de Hidrogênio e interagem hidrofobicamente com resíduos do sub-sítio S1, importantes para a especificidade da enzima, justificando suas atividades inibitórias, enquanto o oxirano-alfa-lapachona não participa de interações importantes. Os resultados de docking molecular no sítio ativo da oligopeptidase B indicaram que o oxirano-alfa-lapachona localiza-se próximo à tríade catalítica da enzima. A análise do complexo mostrou que o mesmo participa de duas ligações de Hidrogênio com os resíduos ARG649 e TYR481 que colaboram com a atividade tripanocida, além de orientarem o anel oxirano com a SER562 da tríade catalítica, indicando um possível ataque nucleofílico (inibição irreversível). A oligopeptidase B não possui enzimas homólogas em humanos, logo é um potencial alvo molecular nos estudos de novos fármacos com atividade tripanocida. Com isso, baseado nas análises realizadas e juntamente com dados obtidos da literatura com relação a inibidores de oligopeptidase B, foram propostos 8 novos derivados do oxirano-alfa-lapachona baseadas em hibridação molecular com a finalidade de aumentar a superfície de contato com o sítio através de interações hidrofóbicas e pontes salinas, descritas na literatura como importantes para a inibição de serino proteases.Programa de Pós-graduação em QuímicaQuímicaRodrigues, Carlos RangelCPF:11122211122http://lattes.cnpq.br/4265523459861860Ferreira, Vítor FranciscoCPF:34985220787http://genos.cnpq.br:12010/dwlattes/owa/prc_imp_cv_int?f_cod=K4783135Y6Frugulhetti, Izabel Christina de Palmer PaixaoCPF:46322264753http://buscatextual.cnpq.br/buscatextual/visualizacv.do?id=K4783557Z4Alencastro, Ricardo Bicca deCPF:02116723787http://lattes.cnpq.br/3981568451860330Villar, José Daniel FigueroaCPF:88168867734http://lattes.cnpq.br/9290362015164639Sant'anna, Carlos Maurício Rabello deCPF:02345678011http://lattes.cnpq.br/2087099684752643Souza, Alessandra Mendonça Teles de2021-03-10T20:50:48Z2014-10-022021-03-10T20:50:48Z2011-06-15info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/doctoralThesisapplication/pdfhttps://app.uff.br/riuff/handle/1/20651porCC-BY-SAinfo:eu-repo/semantics/openAccessreponame:Repositório Institucional da Universidade Federal Fluminense (RIUFF)instname:Universidade Federal Fluminense (UFF)instacron:UFF2021-03-10T20:50:48Zoai:app.uff.br:1/20651Repositório InstitucionalPUBhttps://app.uff.br/oai/requestriuff@id.uff.bropendoar:21202021-03-10T20:50:48Repositório Institucional da Universidade Federal Fluminense (RIUFF) - Universidade Federal Fluminense (UFF)false |
dc.title.none.fl_str_mv |
Modelagem molecular por homologia e estudos de Docking molecular de potenciais alvos terapêuticos para Doença de Chagas Homology molecular modeling and molecular docking studies of potential therapeutic targets for Chagas Disease |
title |
Modelagem molecular por homologia e estudos de Docking molecular de potenciais alvos terapêuticos para Doença de Chagas |
spellingShingle |
Modelagem molecular por homologia e estudos de Docking molecular de potenciais alvos terapêuticos para Doença de Chagas Souza, Alessandra Mendonça Teles de Naftoquinona Modelo molecular Doença de Chagas Naphthoquinone Molecular model Chagas Disease CNPQ::CIENCIAS EXATAS E DA TERRA::QUIMICA |
title_short |
Modelagem molecular por homologia e estudos de Docking molecular de potenciais alvos terapêuticos para Doença de Chagas |
title_full |
Modelagem molecular por homologia e estudos de Docking molecular de potenciais alvos terapêuticos para Doença de Chagas |
title_fullStr |
Modelagem molecular por homologia e estudos de Docking molecular de potenciais alvos terapêuticos para Doença de Chagas |
title_full_unstemmed |
Modelagem molecular por homologia e estudos de Docking molecular de potenciais alvos terapêuticos para Doença de Chagas |
title_sort |
Modelagem molecular por homologia e estudos de Docking molecular de potenciais alvos terapêuticos para Doença de Chagas |
author |
Souza, Alessandra Mendonça Teles de |
author_facet |
Souza, Alessandra Mendonça Teles de |
author_role |
author |
dc.contributor.none.fl_str_mv |
Rodrigues, Carlos Rangel CPF:11122211122 http://lattes.cnpq.br/4265523459861860 Ferreira, Vítor Francisco CPF:34985220787 http://genos.cnpq.br:12010/dwlattes/owa/prc_imp_cv_int?f_cod=K4783135Y6 Frugulhetti, Izabel Christina de Palmer Paixao CPF:46322264753 http://buscatextual.cnpq.br/buscatextual/visualizacv.do?id=K4783557Z4 Alencastro, Ricardo Bicca de CPF:02116723787 http://lattes.cnpq.br/3981568451860330 Villar, José Daniel Figueroa CPF:88168867734 http://lattes.cnpq.br/9290362015164639 Sant'anna, Carlos Maurício Rabello de CPF:02345678011 http://lattes.cnpq.br/2087099684752643 |
dc.contributor.author.fl_str_mv |
Souza, Alessandra Mendonça Teles de |
dc.subject.por.fl_str_mv |
Naftoquinona Modelo molecular Doença de Chagas Naphthoquinone Molecular model Chagas Disease CNPQ::CIENCIAS EXATAS E DA TERRA::QUIMICA |
topic |
Naftoquinona Modelo molecular Doença de Chagas Naphthoquinone Molecular model Chagas Disease CNPQ::CIENCIAS EXATAS E DA TERRA::QUIMICA |
description |
The development of new drugs against Trypanosoma cruzi is still needed since the only drugs used to treat cause serious side effects. Naphthoquinones derivatives β-lapachone and oxiran-alfa-lapachone have high trypanocidal activity and act on different targets in the parasite. With the aim of obtaining parameters that influence the activity profile of these derivatives, computational techniques were used to study the interaction between protease inhibitors and oligopeptidase B and cruzain. In the first part of this work models of oligopeptidase B were built by homology modeling. Due to the low identity with the template 2BKL, models were constructed from alignments performed in ClustalW and 3D-coffee while were used SWISS-MODEL and Modeller programs to obtain three-dimensional structure. After the models validation, the model obtained from SWISS-MODEL and the alignment with ClustalW yielded better results, so it was selected for use in molecular docking studies. In the second part of this work, we studied molecular docking of β- lapachone and oxiran-alfa-lapachone in the active site of cruzain and oligopeptidase B. Studies of molecular docking in the active site of cruzain showed that β-lapachone, E64, a standard cysteine protease inhibitor, are involved in hydrogen bonds and interact hydrophobically with residues of the S1 sub-site, important for the specificity of the enzyme, justifying the inhibitory activity, while the oxiran-alfa lapachone does not participate in important interactions. The results of molecular docking in the active site of oligopeptidase B indicated that the oxiran-alfa-lapachone is located near the catalytic triad of the enzyme. The analysis of the complex showed that it participates in two hydrogen bonds with residues ARG649 and TYR481 corroborate the trypanocidal activity, and guide the oxiran ring with the SER562 the catalytic triad, indicating a possible nucleophilic attack (irreversible inhibition). The oligopeptidase B enzymes do not have homologues in humans, therefore is a potential target in studies of new drugs with trypanocidal activity. Thus, based on tests carried out and jointly with data obtained from the literature of oligopeptidase B inhibitors, 8 new derivatives of oxiran-alfa-lapachone were proposed based on molecular hybridization in order to increase the surface contact with the active site through hydrophobic interactions and salt bridges, as described in the literature as important for the inhibition of serine proteases. |
publishDate |
2011 |
dc.date.none.fl_str_mv |
2011-06-15 2014-10-02 2021-03-10T20:50:48Z 2021-03-10T20:50:48Z |
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 |
https://app.uff.br/riuff/handle/1/20651 |
url |
https://app.uff.br/riuff/handle/1/20651 |
dc.language.iso.fl_str_mv |
por |
language |
por |
dc.rights.driver.fl_str_mv |
CC-BY-SA info:eu-repo/semantics/openAccess |
rights_invalid_str_mv |
CC-BY-SA |
eu_rights_str_mv |
openAccess |
dc.format.none.fl_str_mv |
application/pdf |
dc.publisher.none.fl_str_mv |
Programa de Pós-graduação em Química Química |
publisher.none.fl_str_mv |
Programa de Pós-graduação em Química Química |
dc.source.none.fl_str_mv |
reponame:Repositório Institucional da Universidade Federal Fluminense (RIUFF) instname:Universidade Federal Fluminense (UFF) instacron:UFF |
instname_str |
Universidade Federal Fluminense (UFF) |
instacron_str |
UFF |
institution |
UFF |
reponame_str |
Repositório Institucional da Universidade Federal Fluminense (RIUFF) |
collection |
Repositório Institucional da Universidade Federal Fluminense (RIUFF) |
repository.name.fl_str_mv |
Repositório Institucional da Universidade Federal Fluminense (RIUFF) - Universidade Federal Fluminense (UFF) |
repository.mail.fl_str_mv |
riuff@id.uff.br |
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1807838717089415168 |