Simulação molecular de inibidores da subunidade da ricina, RTA
Autor(a) principal: | |
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Data de Publicação: | 2016 |
Tipo de documento: | Dissertação |
Idioma: | por |
Título da fonte: | Biblioteca Digital de Teses e Dissertações da UFPB |
Texto Completo: | https://repositorio.ufpb.br/jspui/handle/tede/9691 |
Resumo: | Ricinus communis, specifically fruit, castor bean, has gained industry, media and government attention due to the derivate properties such as ricin and castor oil. The total fatty acids xtracted from castor bean, 90% comprises ricinoleic acid. Beyond the castor oil, castor bean processing generate co-products: fruit peel and the castor cake. These co-products present significant amounts of fibers and proteins, in addition to a potential use as nematicide. Since world production of castor oil is 1.5 million tons per year and the proportion of co-product production with castor oil production is approximately 1:1, so, it’s essential to find an economically viable destination for these co-products. In addition to the destinations used, a route with high commercial value would be the use as animal feed, however, this does not occur due to the presence of ricin. Ricin its a ribosome inactivating protein present in the castor bean seed, that consists of two subunits, RTA and RTB, with the RTA being the catalytic subunit. In addition this problem, ricin is used as a biological weapon by terrorists and activists. The inhibition of mechanism of ricin action has biotechnological interest, where RTA is the target for inhibitors synthesis. In this context, the method used to search for new inhibitors its Molecular Docking. This method evaluates thousands of ligands in a short time, however, presents low accuracy in the prediction of binding affinity. In this perspective, SMD simulations can be used. This method is based on the correlation of the mean force profile needed to decouple the ligand from the protein with its affinity. The scientific literature has reported promising results with the approach to discern active binders from inactive. In the present study, beyond the validation data from known RTA inhibitors, the binding affinity potential of 6 novel structures to form complexes with RTA using SMD simulations was evaluated. It was necessary to use Molecular Docking and Molecular Dynamics aproaches to obtain and refine new RTA complexes with novel ligands and next submitted to SMD simulation (k = 2 kcal/mol/Ų, v = 0.005 nm/ps). In addition to the mean force profile obtained from multiple independent SMD simulations, the rupture force and the average of pulling work were measured, these being a direct relation with the binding affinity. In summary, the results of the validation of rupture force and average of pulling work with the experimental data showed a correlation and determination coefficient with R = -0.992 and R² = 0.984 (rupture force) and R -0.958 and R² = 0.918 (average of pulling work), respectively. By means of these validations, the evaluation of novel structures using SMD simulations showed that 4 of the 6 proposed structures present in silico, binding affinity potential for RTA. |
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Simulação molecular de inibidores da subunidade da ricina, RTARicinus communisSteered molecular dynamicsForça de rupturaRicinus communisRicin toxin ASteered molecular dynamicsRupture forceCIENCIAS BIOLOGICASRicinus communis, specifically fruit, castor bean, has gained industry, media and government attention due to the derivate properties such as ricin and castor oil. The total fatty acids xtracted from castor bean, 90% comprises ricinoleic acid. Beyond the castor oil, castor bean processing generate co-products: fruit peel and the castor cake. These co-products present significant amounts of fibers and proteins, in addition to a potential use as nematicide. Since world production of castor oil is 1.5 million tons per year and the proportion of co-product production with castor oil production is approximately 1:1, so, it’s essential to find an economically viable destination for these co-products. In addition to the destinations used, a route with high commercial value would be the use as animal feed, however, this does not occur due to the presence of ricin. Ricin its a ribosome inactivating protein present in the castor bean seed, that consists of two subunits, RTA and RTB, with the RTA being the catalytic subunit. In addition this problem, ricin is used as a biological weapon by terrorists and activists. The inhibition of mechanism of ricin action has biotechnological interest, where RTA is the target for inhibitors synthesis. In this context, the method used to search for new inhibitors its Molecular Docking. This method evaluates thousands of ligands in a short time, however, presents low accuracy in the prediction of binding affinity. In this perspective, SMD simulations can be used. This method is based on the correlation of the mean force profile needed to decouple the ligand from the protein with its affinity. The scientific literature has reported promising results with the approach to discern active binders from inactive. In the present study, beyond the validation data from known RTA inhibitors, the binding affinity potential of 6 novel structures to form complexes with RTA using SMD simulations was evaluated. It was necessary to use Molecular Docking and Molecular Dynamics aproaches to obtain and refine new RTA complexes with novel ligands and next submitted to SMD simulation (k = 2 kcal/mol/Ų, v = 0.005 nm/ps). In addition to the mean force profile obtained from multiple independent SMD simulations, the rupture force and the average of pulling work were measured, these being a direct relation with the binding affinity. In summary, the results of the validation of rupture force and average of pulling work with the experimental data showed a correlation and determination coefficient with R = -0.992 and R² = 0.984 (rupture force) and R -0.958 and R² = 0.918 (average of pulling work), respectively. By means of these validations, the evaluation of novel structures using SMD simulations showed that 4 of the 6 proposed structures present in silico, binding affinity potential for RTA.Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPESA Ricinus communis, especificamente o seu fruto, a mamona, tem ganhado atenção da indústria, mídia e governos, devido as propriedades de seus derivados, especialmente a ricina e o óleo. Do total de ácidos graxos extraídos da mamona, 90% compreende ao ácido ricinoleico. Além do óleo, os coprodutos gerados durante a produção tem ganhado bastante atenção, sendo os mais importantes, a casca do fruto e a torta. Tais coprodutos apresentam quantidades significativas de fibras e proteínas, além de um potencial uso como nematicida. Uma vez que a produção mundial de óleo de mamona é de 1,5 milhão de toneladas-ano e a proporção de produção de coprodutos com a produção de óleo é de aproximadamente 1:1, é fundamental encontrar um destino economicamente viável para esses coprodutos. Além dos destinos utilizados, uma rota com alto valor comercial seria o uso como ração animal, entretanto, isto não ocorre devido a presença da ricina. Esta, corresponde a uma proteína inativadora de ribossomos presente na semente da mamona, e é constituída por duas subunidades, a RTA e RTB, sendo a RTA a subunidade catalítica. Além da problemática supracitada, a ricina é utilizada como arma biológica por terroristas e ativistas, logo, a inibição do mecanismo de ação desta proteína é de grande interesse biotecnológico, sendo a RTA o alvo para síntese de inibidores. Neste aspecto, o método utilizado para busca de novos inibidores é o Atracamento Molecular (Molecular Docking). Este método avalia milhares de ligantes num curto intervalo de tempo, entretanto, apresenta baixa acurácia na predição da afinidade de ligação. Nesta perspectiva, a Dinâmica Molecular Induzida (SMD), pode ser utilizada. Este método baseia-se na correlação do perfil de força médio necessário para desacoplar o ligante da proteína com a sua afinidade. A literatura científica tem relatado resultados promissores no uso dessa abordagem para discernir ligantes ativos de inativos. No presente estudo, além de validações com inibidores de RTA conhecidos, foi avaliado o potencial de afinidade de 6 estruturas inéditas a formarem complexos com a RTA utilizando simulações SMD. Para isso, foi necessário recorrer a abordagens de Atracamento Molecular e Dinâmica Molecular para obtenção e refinamento de novos complexos da RTA com os ligantes candidatos, para somente então, serem submetidos a simulação SMD (k = 2 kcal/mol/Ų, v = 0.005 nm/ps). Neste passo, além do perfil de força médio obtido a partir de múltiplas simulações SMD independentes, foi mensurado a força de ruptura e o trabalho médio realizado pela força, este último, apresenta uma relação direta com a afinidade de ligação pela igualdade de Jarzynski. Em suma, resultados de validação da força de ruptura e trabalho com os dados experimentais mostraram coeficiente de correlação e determinação com R = -0.992 e R² = 0.984 (força de ruptura) e R -0.958 e R² = 0.918 (perfil médio do trabalho), respectivamente. Por meio destas validações, a avaliação dos ligantes candidatos utilizando simulações SMD mostrou que 4 das 6 estruturas propostas, apresentam in silico, potencial de afinidade de ligação para com a RTA.Universidade Federal da ParaíbaBrasilBiotecnologiaPrograma de Pós-Graduação em BiotecnologiaUFPBAraújo, Demetrius Antonio Machado dehttp://lattes.cnpq.br/4795833304329411Rocha, Gerd Bruno dahttp://lattes.cnpq.br/9404945858555096Chaves, Elton Jose Ferreira2017-11-09T14:11:12Z2018-07-20T23:37:34Z2018-07-20T23:37:34Z2016-11-29info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/masterThesisapplication/pdfCHAVES, Elton José Ferreira. Simulação molecular de inibidores da subunidade da ricina, RTA. 2016. 81 f. Dissertação (Mestrado em Biotecnologia) - Universidade Federal da Paraíba, João Pessoa, 2016.https://repositorio.ufpb.br/jspui/handle/tede/9691porhttp://creativecommons.org/licenses/by-nc-nd/4.0/info:eu-repo/semantics/openAccessreponame:Biblioteca Digital de Teses e Dissertações da UFPBinstname:Universidade Federal da Paraíba (UFPB)instacron:UFPB2018-09-06T00:25:24Zoai:repositorio.ufpb.br:tede/9691Biblioteca Digital de Teses e Dissertaçõeshttps://repositorio.ufpb.br/PUBhttp://tede.biblioteca.ufpb.br:8080/oai/requestdiretoria@ufpb.br|| diretoria@ufpb.bropendoar:2018-09-06T00:25:24Biblioteca Digital de Teses e Dissertações da UFPB - Universidade Federal da Paraíba (UFPB)false |
dc.title.none.fl_str_mv |
Simulação molecular de inibidores da subunidade da ricina, RTA |
title |
Simulação molecular de inibidores da subunidade da ricina, RTA |
spellingShingle |
Simulação molecular de inibidores da subunidade da ricina, RTA Chaves, Elton Jose Ferreira Ricinus communis Steered molecular dynamics Força de ruptura Ricinus communis Ricin toxin A Steered molecular dynamics Rupture force CIENCIAS BIOLOGICAS |
title_short |
Simulação molecular de inibidores da subunidade da ricina, RTA |
title_full |
Simulação molecular de inibidores da subunidade da ricina, RTA |
title_fullStr |
Simulação molecular de inibidores da subunidade da ricina, RTA |
title_full_unstemmed |
Simulação molecular de inibidores da subunidade da ricina, RTA |
title_sort |
Simulação molecular de inibidores da subunidade da ricina, RTA |
author |
Chaves, Elton Jose Ferreira |
author_facet |
Chaves, Elton Jose Ferreira |
author_role |
author |
dc.contributor.none.fl_str_mv |
Araújo, Demetrius Antonio Machado de http://lattes.cnpq.br/4795833304329411 Rocha, Gerd Bruno da http://lattes.cnpq.br/9404945858555096 |
dc.contributor.author.fl_str_mv |
Chaves, Elton Jose Ferreira |
dc.subject.por.fl_str_mv |
Ricinus communis Steered molecular dynamics Força de ruptura Ricinus communis Ricin toxin A Steered molecular dynamics Rupture force CIENCIAS BIOLOGICAS |
topic |
Ricinus communis Steered molecular dynamics Força de ruptura Ricinus communis Ricin toxin A Steered molecular dynamics Rupture force CIENCIAS BIOLOGICAS |
description |
Ricinus communis, specifically fruit, castor bean, has gained industry, media and government attention due to the derivate properties such as ricin and castor oil. The total fatty acids xtracted from castor bean, 90% comprises ricinoleic acid. Beyond the castor oil, castor bean processing generate co-products: fruit peel and the castor cake. These co-products present significant amounts of fibers and proteins, in addition to a potential use as nematicide. Since world production of castor oil is 1.5 million tons per year and the proportion of co-product production with castor oil production is approximately 1:1, so, it’s essential to find an economically viable destination for these co-products. In addition to the destinations used, a route with high commercial value would be the use as animal feed, however, this does not occur due to the presence of ricin. Ricin its a ribosome inactivating protein present in the castor bean seed, that consists of two subunits, RTA and RTB, with the RTA being the catalytic subunit. In addition this problem, ricin is used as a biological weapon by terrorists and activists. The inhibition of mechanism of ricin action has biotechnological interest, where RTA is the target for inhibitors synthesis. In this context, the method used to search for new inhibitors its Molecular Docking. This method evaluates thousands of ligands in a short time, however, presents low accuracy in the prediction of binding affinity. In this perspective, SMD simulations can be used. This method is based on the correlation of the mean force profile needed to decouple the ligand from the protein with its affinity. The scientific literature has reported promising results with the approach to discern active binders from inactive. In the present study, beyond the validation data from known RTA inhibitors, the binding affinity potential of 6 novel structures to form complexes with RTA using SMD simulations was evaluated. It was necessary to use Molecular Docking and Molecular Dynamics aproaches to obtain and refine new RTA complexes with novel ligands and next submitted to SMD simulation (k = 2 kcal/mol/Ų, v = 0.005 nm/ps). In addition to the mean force profile obtained from multiple independent SMD simulations, the rupture force and the average of pulling work were measured, these being a direct relation with the binding affinity. In summary, the results of the validation of rupture force and average of pulling work with the experimental data showed a correlation and determination coefficient with R = -0.992 and R² = 0.984 (rupture force) and R -0.958 and R² = 0.918 (average of pulling work), respectively. By means of these validations, the evaluation of novel structures using SMD simulations showed that 4 of the 6 proposed structures present in silico, binding affinity potential for RTA. |
publishDate |
2016 |
dc.date.none.fl_str_mv |
2016-11-29 2017-11-09T14:11:12Z 2018-07-20T23:37:34Z 2018-07-20T23:37:34Z |
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.uri.fl_str_mv |
CHAVES, Elton José Ferreira. Simulação molecular de inibidores da subunidade da ricina, RTA. 2016. 81 f. Dissertação (Mestrado em Biotecnologia) - Universidade Federal da Paraíba, João Pessoa, 2016. https://repositorio.ufpb.br/jspui/handle/tede/9691 |
identifier_str_mv |
CHAVES, Elton José Ferreira. Simulação molecular de inibidores da subunidade da ricina, RTA. 2016. 81 f. Dissertação (Mestrado em Biotecnologia) - Universidade Federal da Paraíba, João Pessoa, 2016. |
url |
https://repositorio.ufpb.br/jspui/handle/tede/9691 |
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por |
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por |
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http://creativecommons.org/licenses/by-nc-nd/4.0/ info:eu-repo/semantics/openAccess |
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http://creativecommons.org/licenses/by-nc-nd/4.0/ |
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openAccess |
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application/pdf |
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Universidade Federal da Paraíba Brasil Biotecnologia Programa de Pós-Graduação em Biotecnologia UFPB |
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Universidade Federal da Paraíba Brasil Biotecnologia Programa de Pós-Graduação em Biotecnologia UFPB |
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Biblioteca Digital de Teses e Dissertações da UFPB - Universidade Federal da Paraíba (UFPB) |
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