Triagem in silico e avaliação in vitro de compostos antifalcizantes
Autor(a) principal: | |
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Data de Publicação: | 2017 |
Tipo de documento: | Tese |
Idioma: | por |
Título da fonte: | Biblioteca Digital de Teses e Dissertações da UEFS |
Texto Completo: | http://localhost:8080/tede/handle/tede/496 |
Resumo: | Adenosine receptors are considered as potential targets for the development of drugs against different pathologies because they are involved in several physiological pathways. Due to the role of adenosine receptors of subtype 2B (RA2B) in the process of sickling cell, antagonists capable of blocking RA2B may be lead compounds for the development of new therapeutic alternatives to treatment of patients with sickle cell anemia. Then, the objective of this work was to identify anti-sickle cell agents capable of blocking RA2B activity. To achieve this goal, was built a pharmacophore model (model 04) capable of differentiating true ligands false-positive (area under the ROC curve = 0.94) and to classify RA2B antagonists, not used in the calibration of the model, regarding their Biological activities pKi = 7.5-9.3 (high potency), 5.5-7.4 (intermediate potency) and 5.4-4.0 (low potency). This pharmacophore model allowed the selection of 33 lead-like compounds from the ZINC database, between them12 compounds presented anti-sickle cell activity. In vitro cell assay with an agonist (NECA) and a RA2B antagonist (MRS1754), suggest that the anti-sickle cell activity is related to modulation of RA2B. Compounds Z1139491704 (pEC50= 7,77±0,17), Z168278894 (pEC50= 7,64±0,09) e Z847449186 (pEC50= 7,66±0,21) have anti-sickling activity Higher than MRS1754 (pEC50= 7,63±0,12) and do not present cytotoxic activity at micromolar range. In sum, it can be concluded that the in silico strategy used succeeded in identifying compounds with probable action antagonists of RA2B that can be considered as prototypes for the development of drugs useful in the treatment of patients with sickle cell anemia. |
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Castilho, Marcelo Santos2015749381481915284520http://lattes.cnpq.br/8201379859412818Paz, Odailson Santos2017-08-08T21:31:24Z2017-05-25PAZ, Odailson Santos. Triagem in silico e avaliação in vitro de compostos antifalcizantes. 2017. 85 f. Tese (Doutorado Acadêmico em Biotecnologia)- Universidade Estadual de Feira de Santana, Feira de Santana, 2017.http://localhost:8080/tede/handle/tede/496Adenosine receptors are considered as potential targets for the development of drugs against different pathologies because they are involved in several physiological pathways. Due to the role of adenosine receptors of subtype 2B (RA2B) in the process of sickling cell, antagonists capable of blocking RA2B may be lead compounds for the development of new therapeutic alternatives to treatment of patients with sickle cell anemia. Then, the objective of this work was to identify anti-sickle cell agents capable of blocking RA2B activity. To achieve this goal, was built a pharmacophore model (model 04) capable of differentiating true ligands false-positive (area under the ROC curve = 0.94) and to classify RA2B antagonists, not used in the calibration of the model, regarding their Biological activities pKi = 7.5-9.3 (high potency), 5.5-7.4 (intermediate potency) and 5.4-4.0 (low potency). This pharmacophore model allowed the selection of 33 lead-like compounds from the ZINC database, between them12 compounds presented anti-sickle cell activity. In vitro cell assay with an agonist (NECA) and a RA2B antagonist (MRS1754), suggest that the anti-sickle cell activity is related to modulation of RA2B. Compounds Z1139491704 (pEC50= 7,77±0,17), Z168278894 (pEC50= 7,64±0,09) e Z847449186 (pEC50= 7,66±0,21) have anti-sickling activity Higher than MRS1754 (pEC50= 7,63±0,12) and do not present cytotoxic activity at micromolar range. In sum, it can be concluded that the in silico strategy used succeeded in identifying compounds with probable action antagonists of RA2B that can be considered as prototypes for the development of drugs useful in the treatment of patients with sickle cell anemia.Os receptores de adenosina são considerados como alvos potenciais para o desenvolvimento de fármacos contra diferentes patologias por estarem envolvidos em diversas vias fisiológicas. Devido ao papel dos receptores de adenosina do subtipo 2B (RA2B) no processo de falcização de hemácias, antagonistas capazes de bloquear RA2B podem ser compostos protótipos para o desenvolvimento de novas alternativas terapêuticas para o tratamento de pacientes com anemia falciforme.Diante desse cenário, o objetivo desse trabalho foi identificar agentes antifalcizantes capazes de antagonizar a atividade do RA2B. Para alcançar esse objetivo foi construído um modelo farmacofórico (modelo 04 - 3 características aceptor e 1 doador de ligação de hidrogênio e 3 centros hidrofóbicos) que é capaz de diferenciar ligantes verdadeiros de falso-positivos (área sob a curva ROC= 0,94)e classificar antagonistas de RA2B,não utilizados na calibração do modelo, quanto as suas atividades biológicas(pKi= 7,5-9,3 (alta potência), 5,5-7,4 (potência intermediária) e 5,4-4,0 (baixa potência)). Esse modelo farmacofórico permitiu a seleção de 33 compostos lead like do banco de dados ZINC database para avaliação biológica, dos quais 12 apresentaram atividade antifalcizante.Testes in vitro com um agonista (NECA) e um antagonista de RA2B (MRS1754), sugerem que a atividade antifalcizante está relacionada a modulação de RA2B.Os compostosZ1139491704(pEC50= 7,77±0,17),Z168278894 (pEC50= 7,64±0,09) e Z847449186 (pEC50= 7,66±0,21)possuem atividade antifalcizante superior ao MRS1754 (pEC50=7,63±0,12)e não apresentam atividade citotóxica em concentrações micromolares. Dessa forma, pode-se concluir que a estratégia in silico utilizada logrou sucesso em identificar compostos com provável ação antagonistas de RA2B que podem ser considerados como protótipos para o desenvolvimento de fármacos úteis no tratamento de pacientes com anemia falciforme.Submitted by Ricardo Cedraz Duque Moliterno (ricardo.moliterno@uefs.br) on 2017-08-08T21:31:24Z No. of bitstreams: 1 TESE_Odailson Paz - com ficha.pdf: 4071411 bytes, checksum: 033f0c18eb721e7010e1ddd7ec27e10c (MD5)Made available in DSpace on 2017-08-08T21:31:24Z (GMT). No. of bitstreams: 1 TESE_Odailson Paz - com ficha.pdf: 4071411 bytes, checksum: 033f0c18eb721e7010e1ddd7ec27e10c (MD5) Previous issue date: 2017-05-25Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPESapplication/pdfporUniversidade Estadual de Feira de SantanaDoutorado Acadêmico em BiotecnologiaUEFSBrasilDEPARTAMENTO DE CIÊNCIAS BIOLÓGICASAnemia falciformeRA2BModelo FarmacofóricoEnsaio virtualAgente AntifalcizanteSickle cell anemiaPharmacophore modelVirtual screeningAnti-sickling AgentCIENCIAS EXATAS E DA TERRA::QUIMICATriagem in silico e avaliação in vitro de compostos antifalcizantesinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/doctoralThesis-6815269229789791543600600600600502612338345058928215717003253031171953590462550136975366info:eu-repo/semantics/openAccessreponame:Biblioteca Digital de Teses e Dissertações da UEFSinstname:Universidade Estadual de Feira de Santana (UEFS)instacron:UEFSORIGINALTESE_Odailson Paz - com ficha.pdfTESE_Odailson Paz - com ficha.pdfapplication/pdf4071411http://tede2.uefs.br:8080/bitstream/tede/496/2/TESE_Odailson+Paz+-+com+ficha.pdf033f0c18eb721e7010e1ddd7ec27e10cMD52LICENSElicense.txtlicense.txttext/plain; charset=utf-82089http://tede2.uefs.br:8080/bitstream/tede/496/1/license.txt7b5ba3d2445355f386edab96125d42b7MD51tede/4962017-08-08 18:31:24.611oai:tede2.uefs.br:8080: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Biblioteca Digital de Teses e Dissertaçõeshttp://tede2.uefs.br:8080/PUBhttp://tede2.uefs.br:8080/oai/requestbcuefs@uefs.br|| bcref@uefs.br||bcuefs@uefs.bropendoar:2017-08-08T21:31:24Biblioteca Digital de Teses e Dissertações da UEFS - Universidade Estadual de Feira de Santana (UEFS)false |
dc.title.por.fl_str_mv |
Triagem in silico e avaliação in vitro de compostos antifalcizantes |
title |
Triagem in silico e avaliação in vitro de compostos antifalcizantes |
spellingShingle |
Triagem in silico e avaliação in vitro de compostos antifalcizantes Paz, Odailson Santos Anemia falciforme RA2B Modelo Farmacofórico Ensaio virtual Agente Antifalcizante Sickle cell anemia Pharmacophore model Virtual screening Anti-sickling Agent CIENCIAS EXATAS E DA TERRA::QUIMICA |
title_short |
Triagem in silico e avaliação in vitro de compostos antifalcizantes |
title_full |
Triagem in silico e avaliação in vitro de compostos antifalcizantes |
title_fullStr |
Triagem in silico e avaliação in vitro de compostos antifalcizantes |
title_full_unstemmed |
Triagem in silico e avaliação in vitro de compostos antifalcizantes |
title_sort |
Triagem in silico e avaliação in vitro de compostos antifalcizantes |
author |
Paz, Odailson Santos |
author_facet |
Paz, Odailson Santos |
author_role |
author |
dc.contributor.advisor1.fl_str_mv |
Castilho, Marcelo Santos |
dc.contributor.advisor1ID.fl_str_mv |
20157493814 |
dc.contributor.authorID.fl_str_mv |
81915284520 |
dc.contributor.authorLattes.fl_str_mv |
http://lattes.cnpq.br/8201379859412818 |
dc.contributor.author.fl_str_mv |
Paz, Odailson Santos |
contributor_str_mv |
Castilho, Marcelo Santos |
dc.subject.por.fl_str_mv |
Anemia falciforme RA2B Modelo Farmacofórico Ensaio virtual Agente Antifalcizante |
topic |
Anemia falciforme RA2B Modelo Farmacofórico Ensaio virtual Agente Antifalcizante Sickle cell anemia Pharmacophore model Virtual screening Anti-sickling Agent CIENCIAS EXATAS E DA TERRA::QUIMICA |
dc.subject.eng.fl_str_mv |
Sickle cell anemia Pharmacophore model Virtual screening Anti-sickling Agent |
dc.subject.cnpq.fl_str_mv |
CIENCIAS EXATAS E DA TERRA::QUIMICA |
description |
Adenosine receptors are considered as potential targets for the development of drugs against different pathologies because they are involved in several physiological pathways. Due to the role of adenosine receptors of subtype 2B (RA2B) in the process of sickling cell, antagonists capable of blocking RA2B may be lead compounds for the development of new therapeutic alternatives to treatment of patients with sickle cell anemia. Then, the objective of this work was to identify anti-sickle cell agents capable of blocking RA2B activity. To achieve this goal, was built a pharmacophore model (model 04) capable of differentiating true ligands false-positive (area under the ROC curve = 0.94) and to classify RA2B antagonists, not used in the calibration of the model, regarding their Biological activities pKi = 7.5-9.3 (high potency), 5.5-7.4 (intermediate potency) and 5.4-4.0 (low potency). This pharmacophore model allowed the selection of 33 lead-like compounds from the ZINC database, between them12 compounds presented anti-sickle cell activity. In vitro cell assay with an agonist (NECA) and a RA2B antagonist (MRS1754), suggest that the anti-sickle cell activity is related to modulation of RA2B. Compounds Z1139491704 (pEC50= 7,77±0,17), Z168278894 (pEC50= 7,64±0,09) e Z847449186 (pEC50= 7,66±0,21) have anti-sickling activity Higher than MRS1754 (pEC50= 7,63±0,12) and do not present cytotoxic activity at micromolar range. In sum, it can be concluded that the in silico strategy used succeeded in identifying compounds with probable action antagonists of RA2B that can be considered as prototypes for the development of drugs useful in the treatment of patients with sickle cell anemia. |
publishDate |
2017 |
dc.date.accessioned.fl_str_mv |
2017-08-08T21:31:24Z |
dc.date.issued.fl_str_mv |
2017-05-25 |
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.citation.fl_str_mv |
PAZ, Odailson Santos. Triagem in silico e avaliação in vitro de compostos antifalcizantes. 2017. 85 f. Tese (Doutorado Acadêmico em Biotecnologia)- Universidade Estadual de Feira de Santana, Feira de Santana, 2017. |
dc.identifier.uri.fl_str_mv |
http://localhost:8080/tede/handle/tede/496 |
identifier_str_mv |
PAZ, Odailson Santos. Triagem in silico e avaliação in vitro de compostos antifalcizantes. 2017. 85 f. Tese (Doutorado Acadêmico em Biotecnologia)- Universidade Estadual de Feira de Santana, Feira de Santana, 2017. |
url |
http://localhost:8080/tede/handle/tede/496 |
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por |
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por |
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600 600 600 600 |
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1571700325303117195 |
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info:eu-repo/semantics/openAccess |
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openAccess |
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application/pdf |
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Universidade Estadual de Feira de Santana |
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Doutorado Acadêmico em Biotecnologia |
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UEFS |
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Brasil |
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DEPARTAMENTO DE CIÊNCIAS BIOLÓGICAS |
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Universidade Estadual de Feira de Santana |
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