Desenvolvimento de modelos de QSAR e análise quimioinformática da sensibilização e permeabilidade da pele

Detalhes bibliográficos
Ano de defesa: 2014
Autor(a) principal: Alves, Vinícius de Medeiros lattes
Orientador(a): Andrade, Carolina Horta lattes
Banca de defesa: Andrade, Carolina Horta, Ferreira, Elizabeth Igne, Camargo, Ademir J.
Tipo de documento: Dissertação
Tipo de acesso: Acesso aberto
Idioma: por
Instituição de defesa: Universidade Federal de Goiás
Programa de Pós-Graduação: Programa de Pós-graduação em Ciências Farmacêuticas (FF)
Departamento: Faculdade Farmácia - FF (RG)
País: Brasil
Palavras-chave em Português:
Palavras-chave em Inglês:
Área do conhecimento CNPq:
Link de acesso: http://repositorio.bc.ufg.br/tede/handle/tde/3028
Resumo: Repetitive exposure to a chemical agent can induce an immune reaction in inherently susceptible individuals that leads to skin sensitization. Although many chemicals have been reported as skin sensitizers, there have been very few reports analyzing the relationships between their molecular structure and the sensitization potential including the connection to skin permeability, which is widely considered to be mechanistically implicated in sensitization. In this study, we have compiled, curated, and integrated the largest publicly available datasets related to chemically-induced skin sensitization and skin permeability. Unexpectedly, no correlation between sensitization and permeability has been found. Predictive QSAR models have been developed and validated for both skin sensitization and skin permeability using a standardized workflow fully compliant with the OECD guidelines. The classification accuracies of QSAR models discriminating sensitizers from non-sensitizers were 0.68-0.88 when evaluated on several external validation sets. When compared to the predictions generated by the OECD QSAR Toolbox skin sensitization module, our models had significantly higher prediction accuracy for the same sets of external compounds as evaluated by Positive Predicted Rate and Negative Predicted Rate as well as Correct Classification Rate. We have also developed QSAR models of skin permeability measured quantitatively. Cross-species correlation between human and rodent permeability data was found to be low (r²=0.44); thus, skin permeability models were developed using human data only and their external accuracy was q²ext = 0.87 (for 62% of external compounds found within the model applicability domain). Skin sensitization models have been employed to identify putative chemical hazards in the Scorecard database of possible skin or sense organ toxicants that should be regarded as primary candidates for the experimental validation.
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spelling Andrade, Carolina Hortahttp://lattes.cnpq.br/2018317447324228Andrade, Carolina HortaFerreira, Elizabeth IgneCamargo, Ademir J.http://lattes.cnpq.br/7314022014345242Alves, Vinícius de Medeiros2014-09-05T20:11:20Z2014-09-052014-03-17ALVES, Vinícius de Medeiros. Desenvolvimento de modelos de QSAR e análise quimioinformática da sensibilização e permeabilidade da pele. 2014. 119 f. Dissertação (Mestrado em Ciências Farmacêuticas) - Universidade Federal de Goiás, Goiânia, 2014.http://repositorio.bc.ufg.br/tede/handle/tde/3028Repetitive exposure to a chemical agent can induce an immune reaction in inherently susceptible individuals that leads to skin sensitization. Although many chemicals have been reported as skin sensitizers, there have been very few reports analyzing the relationships between their molecular structure and the sensitization potential including the connection to skin permeability, which is widely considered to be mechanistically implicated in sensitization. In this study, we have compiled, curated, and integrated the largest publicly available datasets related to chemically-induced skin sensitization and skin permeability. Unexpectedly, no correlation between sensitization and permeability has been found. Predictive QSAR models have been developed and validated for both skin sensitization and skin permeability using a standardized workflow fully compliant with the OECD guidelines. The classification accuracies of QSAR models discriminating sensitizers from non-sensitizers were 0.68-0.88 when evaluated on several external validation sets. When compared to the predictions generated by the OECD QSAR Toolbox skin sensitization module, our models had significantly higher prediction accuracy for the same sets of external compounds as evaluated by Positive Predicted Rate and Negative Predicted Rate as well as Correct Classification Rate. We have also developed QSAR models of skin permeability measured quantitatively. Cross-species correlation between human and rodent permeability data was found to be low (r²=0.44); thus, skin permeability models were developed using human data only and their external accuracy was q²ext = 0.87 (for 62% of external compounds found within the model applicability domain). Skin sensitization models have been employed to identify putative chemical hazards in the Scorecard database of possible skin or sense organ toxicants that should be regarded as primary candidates for the experimental validation.A exposição repetida a agentes químicos pode induzir a sensibilização da pele em indivíduos inerentemente suscetíveis e desencadear uma resposta imunológica exacerbada. Apesar de muitos compostos químicos estarem implicados na sensibilização da pele, existem poucos estudos analisando as relações entre a estrutura molecular e o potencial sensibilizador desses compostos, incluindo a conexão com a permeabilidade pela pele, a qual é referida como sendo primordial para o processo de sensibilização. Neste estudo foram compilados, integrados e preparados os maiores conjuntos de dados disponíveis publicamente relacionados tanto com a sensibilização da pele quanto à permeabilidade. Inesperadamente, não se encontrou correlação entre essas duas propriedades. Modelos de QSAR robustos e preditivos foram gerados e validados para ambas as propriedades usando um fluxo de trabalho totalmente complacente com as recomendações da OECD. As taxas de acerto dos modelos discriminaram estruturas sensibilizadoras de não sensibilizadoras com uma taxa de 0,68-0,88 de sucesso, quando avaliadas em vários conjuntos de validação externa. Quando comparados com o módulo de sensibilização da pele implementado na ferramenta QSAR Toolbox da OECD, os modelos tiveram baixa cobertura do espaço químico, mas precisão preditiva mais elevada para os mesmos conjuntos de compostos externos avaliados pelo valor de preditividade positiva e valor de preditividade negativa assim como pela acurácia balanceada. O coeficiente de correlação cruzada entre os dados de permeabilidade da pele humana e de roedores apresentou-se baixo (r²=0,44); assim, apenas o conjunto de dados de pele humana foi considerado para geração de modelos de permeabilidade, que apresentaram precisão externa de q²ext = 0,87 (para 62% dos compostos dentro do domínio de aplicabilidade). Modelos de sensibilização da pele foram empregados para identificação de toxicantes putativos no banco de dados de possíveis agentes toxicantes da Scorecard que podem ser considerados como candidatos para validação experimental.Submitted by Erika Demachki (erikademachki@gmail.com) on 2014-09-05T20:11:20Z No. of bitstreams: 2 Alves, Vinicius de Medeiros - 2014.pdf: 3082084 bytes, checksum: da4838d5fe24841429f43de84204d98a (MD5) license_rdf: 23148 bytes, checksum: 9da0b6dfac957114c6a7714714b86306 (MD5)Made available in DSpace on 2014-09-05T20:11:20Z (GMT). No. of bitstreams: 2 Alves, Vinicius de Medeiros - 2014.pdf: 3082084 bytes, checksum: da4838d5fe24841429f43de84204d98a (MD5) license_rdf: 23148 bytes, checksum: 9da0b6dfac957114c6a7714714b86306 (MD5) Previous issue date: 2014-03-17Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPESapplication/pdfhttp://repositorio.bc.ufg.br/tede/retrieve/7280/Alves%2c%20Vinicius%20de%20Medeiros%20-%202014.pdf.jpgporUniversidade Federal de GoiásPrograma de Pós-graduação em Ciências Farmacêuticas (FF)UFGBrasilFaculdade Farmácia - FF (RG)ABRAHAM, M. H.; CHADHA, H. S.; MARTINS, F.; MITCHELL, R. C.; BRADBURY, M. W.; GRATTON, J. A. Hydrogen bonding part 46: a review of the correlation and prediction of transport properties by an lfer method: physicochemical properties, brain penetration and skin permeability. Pesticide Science, v. 55, n. 1, p. 78–88, 26 jan. 1999. ADEUSI, S. Pharmaceutical R&D: an organizational design approach to enhancing productivity. 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dc.title.por.fl_str_mv Desenvolvimento de modelos de QSAR e análise quimioinformática da sensibilização e permeabilidade da pele
dc.title.alternative.eng.fl_str_mv Development of QSAR models and cheminformatics analysis of skin sensitization and permeability
title Desenvolvimento de modelos de QSAR e análise quimioinformática da sensibilização e permeabilidade da pele
spellingShingle Desenvolvimento de modelos de QSAR e análise quimioinformática da sensibilização e permeabilidade da pele
Alves, Vinícius de Medeiros
QSAR
Sensibilização da pele
Permeabilidade da pele
Triagem virtual
QSAR modeling
skin sensitization
Skin permeability
Virtual screening
FARMACIA::ANALISE E CONTROLE E MEDICAMENTOS
title_short Desenvolvimento de modelos de QSAR e análise quimioinformática da sensibilização e permeabilidade da pele
title_full Desenvolvimento de modelos de QSAR e análise quimioinformática da sensibilização e permeabilidade da pele
title_fullStr Desenvolvimento de modelos de QSAR e análise quimioinformática da sensibilização e permeabilidade da pele
title_full_unstemmed Desenvolvimento de modelos de QSAR e análise quimioinformática da sensibilização e permeabilidade da pele
title_sort Desenvolvimento de modelos de QSAR e análise quimioinformática da sensibilização e permeabilidade da pele
author Alves, Vinícius de Medeiros
author_facet Alves, Vinícius de Medeiros
author_role author
dc.contributor.advisor1.fl_str_mv Andrade, Carolina Horta
dc.contributor.advisor1Lattes.fl_str_mv http://lattes.cnpq.br/2018317447324228
dc.contributor.referee1.fl_str_mv Andrade, Carolina Horta
dc.contributor.referee2.fl_str_mv Ferreira, Elizabeth Igne
dc.contributor.referee3.fl_str_mv Camargo, Ademir J.
dc.contributor.authorLattes.fl_str_mv http://lattes.cnpq.br/7314022014345242
dc.contributor.author.fl_str_mv Alves, Vinícius de Medeiros
contributor_str_mv Andrade, Carolina Horta
Andrade, Carolina Horta
Ferreira, Elizabeth Igne
Camargo, Ademir J.
dc.subject.por.fl_str_mv QSAR
Sensibilização da pele
Permeabilidade da pele
Triagem virtual
topic QSAR
Sensibilização da pele
Permeabilidade da pele
Triagem virtual
QSAR modeling
skin sensitization
Skin permeability
Virtual screening
FARMACIA::ANALISE E CONTROLE E MEDICAMENTOS
dc.subject.eng.fl_str_mv QSAR modeling
skin sensitization
Skin permeability
Virtual screening
dc.subject.cnpq.fl_str_mv FARMACIA::ANALISE E CONTROLE E MEDICAMENTOS
description Repetitive exposure to a chemical agent can induce an immune reaction in inherently susceptible individuals that leads to skin sensitization. Although many chemicals have been reported as skin sensitizers, there have been very few reports analyzing the relationships between their molecular structure and the sensitization potential including the connection to skin permeability, which is widely considered to be mechanistically implicated in sensitization. In this study, we have compiled, curated, and integrated the largest publicly available datasets related to chemically-induced skin sensitization and skin permeability. Unexpectedly, no correlation between sensitization and permeability has been found. Predictive QSAR models have been developed and validated for both skin sensitization and skin permeability using a standardized workflow fully compliant with the OECD guidelines. The classification accuracies of QSAR models discriminating sensitizers from non-sensitizers were 0.68-0.88 when evaluated on several external validation sets. When compared to the predictions generated by the OECD QSAR Toolbox skin sensitization module, our models had significantly higher prediction accuracy for the same sets of external compounds as evaluated by Positive Predicted Rate and Negative Predicted Rate as well as Correct Classification Rate. We have also developed QSAR models of skin permeability measured quantitatively. Cross-species correlation between human and rodent permeability data was found to be low (r²=0.44); thus, skin permeability models were developed using human data only and their external accuracy was q²ext = 0.87 (for 62% of external compounds found within the model applicability domain). Skin sensitization models have been employed to identify putative chemical hazards in the Scorecard database of possible skin or sense organ toxicants that should be regarded as primary candidates for the experimental validation.
publishDate 2014
dc.date.accessioned.fl_str_mv 2014-09-05T20:11:20Z
dc.date.available.fl_str_mv 2014-09-05
dc.date.issued.fl_str_mv 2014-03-17
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 ALVES, Vinícius de Medeiros. Desenvolvimento de modelos de QSAR e análise quimioinformática da sensibilização e permeabilidade da pele. 2014. 119 f. Dissertação (Mestrado em Ciências Farmacêuticas) - Universidade Federal de Goiás, Goiânia, 2014.
dc.identifier.uri.fl_str_mv http://repositorio.bc.ufg.br/tede/handle/tde/3028
identifier_str_mv ALVES, Vinícius de Medeiros. Desenvolvimento de modelos de QSAR e análise quimioinformática da sensibilização e permeabilidade da pele. 2014. 119 f. Dissertação (Mestrado em Ciências Farmacêuticas) - Universidade Federal de Goiás, Goiânia, 2014.
url http://repositorio.bc.ufg.br/tede/handle/tde/3028
dc.language.iso.fl_str_mv por
language por
dc.relation.program.fl_str_mv 824936988196152412
dc.relation.confidence.fl_str_mv 600
600
600
600
dc.relation.department.fl_str_mv 6010281161524209375
dc.relation.cnpq.fl_str_mv 6216025074656932336
dc.relation.sponsorship.fl_str_mv 2075167498588264571
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