Planejamento in silico de inibidores da enzima dihidrofolato redutase
Autor(a) principal: | |
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Data de Publicação: | 2016 |
Tipo de documento: | Dissertação |
Idioma: | por |
Título da fonte: | Repositório Institucional da UFS |
Texto Completo: | https://ri.ufs.br/handle/riufs/5358 |
Resumo: | Inhibition of the folate metabolism is an important strategy in the treatment of infectious diseases. In the folate metabolism, the dihydrofolate reductase (DHFR) catalyses the reduction of dihydrofolate to tetrahydrofolate. This metabolite is essential for the synthesis of DNA and proteins. Therefore, developing new dihydrofolate reductase antagonist has been considered as a good strategy to improve infectious diseases treatment. In this work, a quantitative study of structure-activity relationship of 17 diaminonazolines inhibitors of the Staphylococcus aureus DHFR (SaDHFR), were performed by using multiple linear regression. Seven inhibitors, not included in the training group, were used to validate the QSAR model. In addition, molecular docking was used to study molecular recognition between SaDHFR and diaminoquinazolines derivatives. Moreover, theoretical pharmacokinetics and toxicological profile was determined for the most potent ligands. The molecular docking study suggest that hydrophobic interactions between the ligand and the residues Ile51, Phe93, Leu55, Val32 and Leu29, are important for potency. The model of QSAR generated values of R2 training, Q2 and R2 pred equal to 0.90, 0.90 and 0.65, respectively. The descriptors included in the model, indicate the importance of pKa and molar refractivity biological activity. The analogs 28A-12, 28A-13 e 28A- 21 exhibit a favorable theoretical pharmacodynamics, pharmacokinetics and toxicological profile. The results obtained for different computational approaches, may be useful in design of new antimicrobial drugs more potent and with few side effects. |
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Matos, Isaac de AraujoCosta Júnior, Nivan Bezerra dahttp://lattes.cnpq.br/81886957243844492017-09-26T18:27:39Z2017-09-26T18:27:39Z2016-02-29Matos, Isaac de Araujo. Planejamento in silico de inibidores da enzima dihidrofolato redutase. 2016. 138 f. Dissertação (Pós-Graduação em Química) - Universidade Federal de Sergipe, São Cristóvão, 2016.https://ri.ufs.br/handle/riufs/5358Inhibition of the folate metabolism is an important strategy in the treatment of infectious diseases. In the folate metabolism, the dihydrofolate reductase (DHFR) catalyses the reduction of dihydrofolate to tetrahydrofolate. This metabolite is essential for the synthesis of DNA and proteins. Therefore, developing new dihydrofolate reductase antagonist has been considered as a good strategy to improve infectious diseases treatment. In this work, a quantitative study of structure-activity relationship of 17 diaminonazolines inhibitors of the Staphylococcus aureus DHFR (SaDHFR), were performed by using multiple linear regression. Seven inhibitors, not included in the training group, were used to validate the QSAR model. In addition, molecular docking was used to study molecular recognition between SaDHFR and diaminoquinazolines derivatives. Moreover, theoretical pharmacokinetics and toxicological profile was determined for the most potent ligands. The molecular docking study suggest that hydrophobic interactions between the ligand and the residues Ile51, Phe93, Leu55, Val32 and Leu29, are important for potency. The model of QSAR generated values of R2 training, Q2 and R2 pred equal to 0.90, 0.90 and 0.65, respectively. The descriptors included in the model, indicate the importance of pKa and molar refractivity biological activity. The analogs 28A-12, 28A-13 e 28A- 21 exhibit a favorable theoretical pharmacodynamics, pharmacokinetics and toxicological profile. The results obtained for different computational approaches, may be useful in design of new antimicrobial drugs more potent and with few side effects.A inibição do metabolismo do folato é uma importante estratégia no tratamento de doenças infecciosas. No metabolismo do folato, a enzima diidrofolato redutase (DHFR) catalisa a redução do diidrofolato a tetraidrofolato. Este metabólito é essencial para a biossíntese de DNA e proteínas. Portanto, o desenvolvimento de novos antagonistas da diidrofolato redutase tem sido considerado como uma boa estratégia para melhorar o tratamento das doenças infecciosas. No presente trabalho, foi desenvolvido uma relação estruturaatividade a partir de 17 diaminoquinazolinas inibidoras da DHFR do Staphylococcus aureus (SaDHFR) empregando para isso, a regressão linear múltipla. Sete inibidores, não incluídos no grupo treino foram usados para validar o modelo de QSAR. Em adição, docagem molecular foi empregada para avaliar o reconhecimento molecular entre a SaDHFR e a série de diaminoquinazolinas. Além disso, os perfis farmacocinéticos e toxicológicos teóricos foram avaliados para os ligantes mais potentes. Os resultados obtidos por docagem molecular sugerem que as interações hidrofóbicas entre os ligantes e os resíduos Ile51, Phe93, Leu55, Val32 e Leu29, são importantes para a potência dos ligantes. O modelo de QSAR desenvolvido apresentou valores de R2treino, Q2 e R2pred igual a 0.90, 0.90 e 0.65, respectivamente. Os descritores incluídos no modelo, indicam a importância do pKa e da refratividade para a atividade biológica. Os análogos 28A-12, 28A-13 e 28A-21 exibem um perfil farmacodinâmico, farmacocinético e toxicológico favorável. Os resultados obtidos por meio de diferentes abordagens computacionais podem ser úteis no planejamento de novos fármacos antimicrobianos mais potentes e com menos efeitos colaterais.Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPESapplication/pdfporUniversidade Federal de SergipePós-Graduação em QuímicaUFSBrasilQuímicaInibidoresDiidrofolato redutaseStaphylococcus aureusDiaminoquinazolinasDocagem molecularMetabolismo do folatoCIENCIAS EXATAS E DA TERRA::QUIMICAPlanejamento in silico de inibidores da enzima dihidrofolato redutaseDrug design in silico of dihydrofolate reductase inhibitorsinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/masterThesisinfo:eu-repo/semantics/openAccessreponame:Repositório Institucional da UFSinstname:Universidade Federal de Sergipe (UFS)instacron:UFSORIGINALISAAC_ARAUJO_MATOS.pdfapplication/pdf5356474https://ri.ufs.br/jspui/bitstream/riufs/5358/1/ISAAC_ARAUJO_MATOS.pdf035e502b6e013750f41113031ccf5fcdMD51TEXTISAAC_ARAUJO_MATOS.pdf.txtISAAC_ARAUJO_MATOS.pdf.txtExtracted texttext/plain216973https://ri.ufs.br/jspui/bitstream/riufs/5358/2/ISAAC_ARAUJO_MATOS.pdf.txt323afae094f4d0f15fb7158e4ce1d343MD52THUMBNAILISAAC_ARAUJO_MATOS.pdf.jpgISAAC_ARAUJO_MATOS.pdf.jpgGenerated Thumbnailimage/jpeg1486https://ri.ufs.br/jspui/bitstream/riufs/5358/3/ISAAC_ARAUJO_MATOS.pdf.jpgcda4b03580938a3be1cf5b18ed3e94e7MD53riufs/53582018-01-16 19:59:29.803oai:ufs.br:riufs/5358Repositório InstitucionalPUBhttps://ri.ufs.br/oai/requestrepositorio@academico.ufs.bropendoar:2018-01-16T22:59:29Repositório Institucional da UFS - Universidade Federal de Sergipe (UFS)false |
dc.title.por.fl_str_mv |
Planejamento in silico de inibidores da enzima dihidrofolato redutase |
dc.title.alternative.eng.fl_str_mv |
Drug design in silico of dihydrofolate reductase inhibitors |
title |
Planejamento in silico de inibidores da enzima dihidrofolato redutase |
spellingShingle |
Planejamento in silico de inibidores da enzima dihidrofolato redutase Matos, Isaac de Araujo Química Inibidores Diidrofolato redutase Staphylococcus aureus Diaminoquinazolinas Docagem molecular Metabolismo do folato CIENCIAS EXATAS E DA TERRA::QUIMICA |
title_short |
Planejamento in silico de inibidores da enzima dihidrofolato redutase |
title_full |
Planejamento in silico de inibidores da enzima dihidrofolato redutase |
title_fullStr |
Planejamento in silico de inibidores da enzima dihidrofolato redutase |
title_full_unstemmed |
Planejamento in silico de inibidores da enzima dihidrofolato redutase |
title_sort |
Planejamento in silico de inibidores da enzima dihidrofolato redutase |
author |
Matos, Isaac de Araujo |
author_facet |
Matos, Isaac de Araujo |
author_role |
author |
dc.contributor.author.fl_str_mv |
Matos, Isaac de Araujo |
dc.contributor.advisor1.fl_str_mv |
Costa Júnior, Nivan Bezerra da |
dc.contributor.authorLattes.fl_str_mv |
http://lattes.cnpq.br/8188695724384449 |
contributor_str_mv |
Costa Júnior, Nivan Bezerra da |
dc.subject.por.fl_str_mv |
Química Inibidores Diidrofolato redutase Staphylococcus aureus Diaminoquinazolinas Docagem molecular Metabolismo do folato |
topic |
Química Inibidores Diidrofolato redutase Staphylococcus aureus Diaminoquinazolinas Docagem molecular Metabolismo do folato CIENCIAS EXATAS E DA TERRA::QUIMICA |
dc.subject.cnpq.fl_str_mv |
CIENCIAS EXATAS E DA TERRA::QUIMICA |
description |
Inhibition of the folate metabolism is an important strategy in the treatment of infectious diseases. In the folate metabolism, the dihydrofolate reductase (DHFR) catalyses the reduction of dihydrofolate to tetrahydrofolate. This metabolite is essential for the synthesis of DNA and proteins. Therefore, developing new dihydrofolate reductase antagonist has been considered as a good strategy to improve infectious diseases treatment. In this work, a quantitative study of structure-activity relationship of 17 diaminonazolines inhibitors of the Staphylococcus aureus DHFR (SaDHFR), were performed by using multiple linear regression. Seven inhibitors, not included in the training group, were used to validate the QSAR model. In addition, molecular docking was used to study molecular recognition between SaDHFR and diaminoquinazolines derivatives. Moreover, theoretical pharmacokinetics and toxicological profile was determined for the most potent ligands. The molecular docking study suggest that hydrophobic interactions between the ligand and the residues Ile51, Phe93, Leu55, Val32 and Leu29, are important for potency. The model of QSAR generated values of R2 training, Q2 and R2 pred equal to 0.90, 0.90 and 0.65, respectively. The descriptors included in the model, indicate the importance of pKa and molar refractivity biological activity. The analogs 28A-12, 28A-13 e 28A- 21 exhibit a favorable theoretical pharmacodynamics, pharmacokinetics and toxicological profile. The results obtained for different computational approaches, may be useful in design of new antimicrobial drugs more potent and with few side effects. |
publishDate |
2016 |
dc.date.issued.fl_str_mv |
2016-02-29 |
dc.date.accessioned.fl_str_mv |
2017-09-26T18:27:39Z |
dc.date.available.fl_str_mv |
2017-09-26T18:27:39Z |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/masterThesis |
format |
masterThesis |
status_str |
publishedVersion |
dc.identifier.citation.fl_str_mv |
Matos, Isaac de Araujo. Planejamento in silico de inibidores da enzima dihidrofolato redutase. 2016. 138 f. Dissertação (Pós-Graduação em Química) - Universidade Federal de Sergipe, São Cristóvão, 2016. |
dc.identifier.uri.fl_str_mv |
https://ri.ufs.br/handle/riufs/5358 |
identifier_str_mv |
Matos, Isaac de Araujo. Planejamento in silico de inibidores da enzima dihidrofolato redutase. 2016. 138 f. Dissertação (Pós-Graduação em Química) - Universidade Federal de Sergipe, São Cristóvão, 2016. |
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https://ri.ufs.br/handle/riufs/5358 |
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Universidade Federal de Sergipe |
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Pós-Graduação em Química |
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UFS |
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Brasil |
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Universidade Federal de Sergipe |
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