Modelagem molecular de derivados pirimidínicos e estudos de docking nas enzimas ciclooxigenase 1 e ciclooxigenase 2
Autor(a) principal: | |
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Data de Publicação: | 2010 |
Tipo de documento: | Dissertação |
Idioma: | por |
Título da fonte: | Repositório Institucional da UFSCAR |
Texto Completo: | https://repositorio.ufscar.br/handle/ufscar/6975 |
Resumo: | In this research molecular docking was used to study enzime-ligand complexes of Cyclooxygenase 1 (COX-1) and Cyclooxygenase 2 (COX-2) with pyrimidine derivatives, aiming at understanding the possible mechanisms of action of these compounds and, thus, suggest modifications that could increase their specificity. The chosen ligands were a series of 25 substituted pyrimidines with known activity. The three-dimensional structures of these compounds were obtained by molecular modeling and that of the enzymes from the PDB and PDBSum under the codes 2OYE and 1CX2 for COX-1 and COX-2 respectively. The binding sites chosen for the docking studies were 20 Å around the crystallographic ligands IM8-700 (2OYE) and SC-558 (1CX2). In the COX-1 formed complexes the SO2Me moiety is positioned in such a way as to form hydrogen bonds with Ile517 and Phe518. The benzo[b]thiophen-2-ylmethyl-[2-(4-methanesulfonylphenyl)-6-trifluoromethylpyrimidin-4- yl]amine formed the most favorable complex with COX-1. In COX-2, the enzyme-ligand interaction pattern shows the SO2Me group in the side pocket, forming hydrogen bonds with His90 and Arg513 and the different substituent groups of the pyrimidine ring form hydrogen bonds with Arg120 and Tyr355. The presence of a small lipophilic pocket in COX-2 and the docking results suggest that the ligands 2, 15, 17, 22 and 23 may have their activity enhanced by the addition of a hydrophobic group on the phenyl or thiophenyl rings so this group can interact within this pocket. In both cases the mechanism of inhibition is probably competitive. As the search for new anti-inflammatory drugs must deal with a subtle balance of COX-2 and COX-1 inhibitions, the ligands 2 and 22 that showed better results for COX-2 rather than for COX-1 would be the most promising ones and therefore, those that should be tested in vivo. |
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Armelin, Paulo Roberto GabbaiSchpector, Júlio Zukermanhttp://lattes.cnpq.br/4252331837170383http://lattes.cnpq.br/34054586262192522016-08-17T18:39:37Z2011-05-302016-08-17T18:39:37Z2010-11-23ARMELIN, Paulo Roberto Gabbai. Molecular Modeling of pyrimidine derivatives and docking studies in the enzymes cyclooxygenases 1 and 2. 2010. 124 f. Dissertação (Mestrado em Multidisciplinar) - Universidade Federal de São Carlos, São Carlos, 2010.https://repositorio.ufscar.br/handle/ufscar/6975In this research molecular docking was used to study enzime-ligand complexes of Cyclooxygenase 1 (COX-1) and Cyclooxygenase 2 (COX-2) with pyrimidine derivatives, aiming at understanding the possible mechanisms of action of these compounds and, thus, suggest modifications that could increase their specificity. The chosen ligands were a series of 25 substituted pyrimidines with known activity. The three-dimensional structures of these compounds were obtained by molecular modeling and that of the enzymes from the PDB and PDBSum under the codes 2OYE and 1CX2 for COX-1 and COX-2 respectively. The binding sites chosen for the docking studies were 20 Å around the crystallographic ligands IM8-700 (2OYE) and SC-558 (1CX2). In the COX-1 formed complexes the SO2Me moiety is positioned in such a way as to form hydrogen bonds with Ile517 and Phe518. The benzo[b]thiophen-2-ylmethyl-[2-(4-methanesulfonylphenyl)-6-trifluoromethylpyrimidin-4- yl]amine formed the most favorable complex with COX-1. In COX-2, the enzyme-ligand interaction pattern shows the SO2Me group in the side pocket, forming hydrogen bonds with His90 and Arg513 and the different substituent groups of the pyrimidine ring form hydrogen bonds with Arg120 and Tyr355. The presence of a small lipophilic pocket in COX-2 and the docking results suggest that the ligands 2, 15, 17, 22 and 23 may have their activity enhanced by the addition of a hydrophobic group on the phenyl or thiophenyl rings so this group can interact within this pocket. In both cases the mechanism of inhibition is probably competitive. As the search for new anti-inflammatory drugs must deal with a subtle balance of COX-2 and COX-1 inhibitions, the ligands 2 and 22 that showed better results for COX-2 rather than for COX-1 would be the most promising ones and therefore, those that should be tested in vivo.Neste trabalho, o docking molecular foi utilizado para o estudo da formação de complexos alvoligante das enzimas Ciclooxigenase 1 (COX-1) e Ciclooxigenase 2 (COX-2) com derivados pirimidínicos, com a finalidade de entender os possíveis mecanismos de ação e, assim, propor modificações nos compostos visando diminuir prováveis efeitos colaterais. Os ligantes escolhidos foram uma série de 25 pirimidinas substituídas com atividade conhecida. As estruturas tridimensionais destas moléculas foram obtidas por modelagem molecular e as das enzimas dos bancos de dados PDB e PDBSum sob o código 2OYE e 1CX2 para COX-1 e COX- 2 respectivamente. Os sítios de ligação escolhidos para os cálculos de docking foram de 20 Å ao redor dos ligantes cristalográficos IM8-700 (2OYE) e SC-558 (1CX2). Das pirimidinas analisadas as que formaram complexo com a COX-1 se orientaram com a porção SO2Me formando ligações de hidrogênio com a Ile517 e Phe518. Sendo o benzo[b]tiofen-2-ilmetil-2-(4- metanosulfonilfenil)-6-trifluorometilpirimidina-4-il]amina o mais favorável para a formação de complexo com a COX-1. Para a COX-2, os compostos que se ligaram mostram um padrão que inclui ligações de hidrogênio entre a porção SO2Me e a His90 e Arg513 do bolso lateral e entre a Arg120 e Tyr355 com os grupos substituintes do anel pirimidínico. A presença de um pequeno bolso lipofílico na COX-2 e os resultados de docking permitem sugerir que os ligantes 2, 15, 17, 22 e 23 poderiam mostrar melhor atividade mediante a adição de um grupo hidrofóbico no anel fenila ou tiofenila para que este grupo se posicione dentro desse bolso. Em ambos os casos o tipo de inibição provável é o competitivo. Como a busca por novos fármacos antiinflamatórios deve lidar com um equilíbrio entre a inibição de COX-2 e COX-1, os ligantes 2 e 22 que apresentaram resultados favoráveis para a COX-2 e não tanto para a COX-1 seriam os mais promissores e, portanto, aqueles que poderiam ser testados in vivo.Financiadora de Estudos e Projetosapplication/pdfporUniversidade Federal de São CarlosPrograma de Pós-Graduação em Biotecnologia - PPGBiotecUFSCarBRBiotecnologiaCiclooxigenase 1Ciclooxigenase 2PirimidinasDockingModelagem molecularCyclooxygenase 1Cyclooxygenase 2PyrimidinesDockingMolecular modelingOUTROSModelagem molecular de derivados pirimidínicos e estudos de docking nas enzimas ciclooxigenase 1 e ciclooxigenase 2Molecular Modeling of pyrimidine derivatives and docking studies in the enzymes cyclooxygenases 1 and 2info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/masterThesisinfo:eu-repo/semantics/openAccessreponame:Repositório Institucional da UFSCARinstname:Universidade Federal de São Carlos (UFSCAR)instacron:UFSCARORIGINAL3649.pdfapplication/pdf6160139https://{{ getenv "DSPACE_HOST" "repositorio.ufscar.br" }}/bitstream/ufscar/6975/1/3649.pdfe2fc962eefef9b03fa83e0311a505531MD51TEXT3649.pdf.txt3649.pdf.txtExtracted texttext/plain181797https://{{ getenv "DSPACE_HOST" "repositorio.ufscar.br" }}/bitstream/ufscar/6975/2/3649.pdf.txtb555cee8bd43dba32514841f4413eacbMD52THUMBNAIL3649.pdf.jpg3649.pdf.jpgIM Thumbnailimage/jpeg9312https://{{ getenv "DSPACE_HOST" "repositorio.ufscar.br" }}/bitstream/ufscar/6975/3/3649.pdf.jpg176c0704b9719a5de99bc1ccf8e77babMD53ufscar/69752020-03-23 19:42:14.171oai:repositorio.ufscar.br:ufscar/6975Repositório InstitucionalPUBhttps://repositorio.ufscar.br/oai/requestopendoar:43222020-03-23T19:42:14Repositório Institucional da UFSCAR - Universidade Federal de São Carlos (UFSCAR)false |
dc.title.por.fl_str_mv |
Modelagem molecular de derivados pirimidínicos e estudos de docking nas enzimas ciclooxigenase 1 e ciclooxigenase 2 |
dc.title.alternative.eng.fl_str_mv |
Molecular Modeling of pyrimidine derivatives and docking studies in the enzymes cyclooxygenases 1 and 2 |
title |
Modelagem molecular de derivados pirimidínicos e estudos de docking nas enzimas ciclooxigenase 1 e ciclooxigenase 2 |
spellingShingle |
Modelagem molecular de derivados pirimidínicos e estudos de docking nas enzimas ciclooxigenase 1 e ciclooxigenase 2 Armelin, Paulo Roberto Gabbai Biotecnologia Ciclooxigenase 1 Ciclooxigenase 2 Pirimidinas Docking Modelagem molecular Cyclooxygenase 1 Cyclooxygenase 2 Pyrimidines Docking Molecular modeling OUTROS |
title_short |
Modelagem molecular de derivados pirimidínicos e estudos de docking nas enzimas ciclooxigenase 1 e ciclooxigenase 2 |
title_full |
Modelagem molecular de derivados pirimidínicos e estudos de docking nas enzimas ciclooxigenase 1 e ciclooxigenase 2 |
title_fullStr |
Modelagem molecular de derivados pirimidínicos e estudos de docking nas enzimas ciclooxigenase 1 e ciclooxigenase 2 |
title_full_unstemmed |
Modelagem molecular de derivados pirimidínicos e estudos de docking nas enzimas ciclooxigenase 1 e ciclooxigenase 2 |
title_sort |
Modelagem molecular de derivados pirimidínicos e estudos de docking nas enzimas ciclooxigenase 1 e ciclooxigenase 2 |
author |
Armelin, Paulo Roberto Gabbai |
author_facet |
Armelin, Paulo Roberto Gabbai |
author_role |
author |
dc.contributor.authorlattes.por.fl_str_mv |
http://lattes.cnpq.br/3405458626219252 |
dc.contributor.author.fl_str_mv |
Armelin, Paulo Roberto Gabbai |
dc.contributor.advisor1.fl_str_mv |
Schpector, Júlio Zukerman |
dc.contributor.advisor1Lattes.fl_str_mv |
http://lattes.cnpq.br/4252331837170383 |
contributor_str_mv |
Schpector, Júlio Zukerman |
dc.subject.por.fl_str_mv |
Biotecnologia Ciclooxigenase 1 Ciclooxigenase 2 Pirimidinas Docking Modelagem molecular |
topic |
Biotecnologia Ciclooxigenase 1 Ciclooxigenase 2 Pirimidinas Docking Modelagem molecular Cyclooxygenase 1 Cyclooxygenase 2 Pyrimidines Docking Molecular modeling OUTROS |
dc.subject.eng.fl_str_mv |
Cyclooxygenase 1 Cyclooxygenase 2 Pyrimidines Docking Molecular modeling |
dc.subject.cnpq.fl_str_mv |
OUTROS |
description |
In this research molecular docking was used to study enzime-ligand complexes of Cyclooxygenase 1 (COX-1) and Cyclooxygenase 2 (COX-2) with pyrimidine derivatives, aiming at understanding the possible mechanisms of action of these compounds and, thus, suggest modifications that could increase their specificity. The chosen ligands were a series of 25 substituted pyrimidines with known activity. The three-dimensional structures of these compounds were obtained by molecular modeling and that of the enzymes from the PDB and PDBSum under the codes 2OYE and 1CX2 for COX-1 and COX-2 respectively. The binding sites chosen for the docking studies were 20 Å around the crystallographic ligands IM8-700 (2OYE) and SC-558 (1CX2). In the COX-1 formed complexes the SO2Me moiety is positioned in such a way as to form hydrogen bonds with Ile517 and Phe518. The benzo[b]thiophen-2-ylmethyl-[2-(4-methanesulfonylphenyl)-6-trifluoromethylpyrimidin-4- yl]amine formed the most favorable complex with COX-1. In COX-2, the enzyme-ligand interaction pattern shows the SO2Me group in the side pocket, forming hydrogen bonds with His90 and Arg513 and the different substituent groups of the pyrimidine ring form hydrogen bonds with Arg120 and Tyr355. The presence of a small lipophilic pocket in COX-2 and the docking results suggest that the ligands 2, 15, 17, 22 and 23 may have their activity enhanced by the addition of a hydrophobic group on the phenyl or thiophenyl rings so this group can interact within this pocket. In both cases the mechanism of inhibition is probably competitive. As the search for new anti-inflammatory drugs must deal with a subtle balance of COX-2 and COX-1 inhibitions, the ligands 2 and 22 that showed better results for COX-2 rather than for COX-1 would be the most promising ones and therefore, those that should be tested in vivo. |
publishDate |
2010 |
dc.date.issued.fl_str_mv |
2010-11-23 |
dc.date.available.fl_str_mv |
2011-05-30 2016-08-17T18:39:37Z |
dc.date.accessioned.fl_str_mv |
2016-08-17T18:39:37Z |
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 |
ARMELIN, Paulo Roberto Gabbai. Molecular Modeling of pyrimidine derivatives and docking studies in the enzymes cyclooxygenases 1 and 2. 2010. 124 f. Dissertação (Mestrado em Multidisciplinar) - Universidade Federal de São Carlos, São Carlos, 2010. |
dc.identifier.uri.fl_str_mv |
https://repositorio.ufscar.br/handle/ufscar/6975 |
identifier_str_mv |
ARMELIN, Paulo Roberto Gabbai. Molecular Modeling of pyrimidine derivatives and docking studies in the enzymes cyclooxygenases 1 and 2. 2010. 124 f. Dissertação (Mestrado em Multidisciplinar) - Universidade Federal de São Carlos, São Carlos, 2010. |
url |
https://repositorio.ufscar.br/handle/ufscar/6975 |
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por |
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openAccess |
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dc.publisher.none.fl_str_mv |
Universidade Federal de São Carlos |
dc.publisher.program.fl_str_mv |
Programa de Pós-Graduação em Biotecnologia - PPGBiotec |
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UFSCar |
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BR |
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Universidade Federal de São Carlos |
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