1. TEDE
  2. CAMPUS SEROPÉDICA
  3. Programa de Pós-Graduação em Química
  4. Doutorado em Química
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dc.creatorDel Cistia, Catarina De Nigris-
dc.creator.Latteshttp://lattes.cnpq.br/3406739726482067por
dc.contributor.advisor1Sant'Anna, Carlos Mauricio Rabello de-
dc.contributor.advisor1Latteshttp://lattes.cnpq.br/2087099684752643por
dc.contributor.advisor-co1Echevarria, Aurea-
dc.contributor.referee1Graebin, Cedric Estephan-
dc.contributor.referee2Leon, Leonor Laura Pinto-
dc.contributor.referee3Romeiro, Nelilma Correia-
dc.date.accessioned2019-05-23T13:49:15Z-
dc.date.issued2010-06-11-
dc.identifier.citationDEL CISTIA, Catarina De Nigris. Modelagem molecular aplicada ao estudo de reações de inibição enzimática com aplicação potencial no controle de Leishmania amazonensis. 2010. 219 f. Tese (Doutorado em Química) - Instituto de Ciências Exatas, Universidade Federal Rural do Rio de Janeiro, Seropédica, 2010.por
dc.identifier.urihttps://tede.ufrrj.br/jspui/handle/jspui/2713-
dc.description.resumoAs doenças provocadas por protozoários, transmitidas principalmente por insetos hematófagos, constituem o problema de saúde humana mais distribuído no mundo, e estimase que três milhões de indivíduos sofram de uma doença parasitária (principalmente pelos tripanossomatídeos e apicomplexa), responsáveis por importantes doenças humanas. Os compostos aqui estudados constituem as amidinas e os mesoiônicos, ambos sintetizados por Echevarria e colaboradores, UFRRJ. Este trabalho possui, como proposta inicial, uma procura por relações e equações que possuam boa correlação entre os valores de “ln(IC50)” calculados e os valores de “ln(IC50)” determinados experimentalmente, para determinar se o composto será ou não capaz de inibir as enzimas NO sintase (NOS) e tripanotiona redutase (TR) (em relação a enzimas pertencentes à Leishmania amazonensis). Como não há estruturas disponíveis da enzima TR para este organismo, um modelo foi feito através da técnica de modelagem por homologia, com um sequenciamento feito por laboratórios da FIOCRUZ [CASTRO-PINTO et al., 2008]. Esta estrutura foi usada para chegarmos aos resultados voltados realmente à Leishmania. As correlações foram procuradas através de 2 métodos diferentes: através do método de atracamento molecular (ou “docking”) e do método semiempírico (com hamiltoniano PM3 [STEWART, 1989a,b]). Através destes métodos, foi analisada a probabilidade destes compostos se complexarem ao sítio ativo (como um inibidor isostérico), ou aos sítios do FAD e NADPH (como um inibidor alostérico). Frente aos compostos de atividade já conhecida analisados para montar o esquema (as fenotiazinas), encontrou-se que estes compostos se complexam melhor ao sítio ativo, atuando como inibidores isostéricos; porém os mesoiônicos e amidinas se complexam melhor ao sítio do FAD, caracterizando uma inibição alostérica. Frente ao padrão de atracamento destas moléculas no respectivo sítio, alterações foram propostas em suas estruturas básicas para fazer com que fiquem ainda mais ativos. Com isto, foram encontradas equações que possuem alta correlação entre os valores de ln(IC50) experimentais e calculados, fazendo com que estas equações possam ser usadas para a síntese de estruturas mais ativas, com menos efeitos colaterais.por
dc.description.abstractParasitic protozoan diseases, transmitted by blood-feeding insects, constitute the world’s most widely spread human health problem. It is estimated that three million people suffer from a parasitic infection (mainly trypanosomatid and apicomplexan parasites), responsible for important human diseases. The compounds here studied constitute the amidines and the mesoionics, synthesized by Echevarria and collaborators, UFRRJ. This work constitute, as an initial proposal, a search for relationships and equations that has good correlation between the calculated and experimental “ln(IC50)” values, to determinate the NO synthase (NOS) and trypanothione reductase (TR) inhibition capacity of the compounds (Leishmania amazonensis enzymes). A model was made through the homology modeling method, with a sequence made by FIOCRUZ laboratories [CASTRO-PINTO et al., 2008], as there are no TR enzyme available structures for this organism. This structure was used to get results really focused on Leishmania. The correlations were searched through 2 different methods: docking and semi-empirical methods (with PM3 parametric model [STEWART, 1989a,b]). Through these methods, the compounds active site binding probability (as an isosteric inhibitor) and the FAD and NADPH site binding probability (as an allosteric inhibitor) was analyzed. With the known activity compounds (the phenothiazines) used to build the model, the results shown that these compounds are better docked at the active site, acting as an isosteric inhibitor. However, the mesoionics and amidines dock better at the FAD binding site, featuring an allosteric inhibition. Through these molecules docking pattern at this binding site, structural alterations were proposed to make them even more active. High correlation equations were found between calculated and experimental ln(IC50). These equations can now be used for more active compounds synthesis, with less side effects.eng
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dc.description.sponsorshipCoordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPESpor
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dc.languageporpor
dc.publisherUniversidade Federal Rural do Rio de Janeiropor
dc.publisher.departmentInstituto de Ciências Exataspor
dc.publisher.countryBrasilpor
dc.publisher.initialsUFRRJpor
dc.publisher.programPrograma de Pós-Graduação em Químicapor
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dc.rightsAcesso Abertopor
dc.subjectLeishmania amazonensispor
dc.subjectmodelagem molecularpor
dc.subjectmesoiônicospor
dc.subjectamidinaspor
dc.subjectLeishmania amazonensiseng
dc.subjectmolecular modelingeng
dc.subjectmesoionicseng
dc.subjectamidineseng
dc.subject.cnpqQuímicapor
dc.titleModelagem molecular aplicada ao estudo de reações de inibição enzimática com aplicação potencial no controle de Leishmania amazonensispor
dc.title.alternativeApplied molecular modeling to the enzymatic inhibition reactions study with Leishmania amazonensis control’s potential applicationeng
dc.typeTesepor
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