Planejamento e identificação de novos agentes esquistossomicidas a partir de estratégias em química medicinal

• Autor(a) principal: Melo Filho, Cleber Camilo de
• Data de Publicação: 2014
• Tipo de documento: Dissertação
• Idioma: por
• Título da fonte: Repositório Institucional da UFG
• dARK ID: ark:/38995/0013000005gpd
• Texto Completo: http://repositorio.bc.ufg.br/tede/handle/tede/3614
• topic: Esquistossomose; Schistosoma mansoni; Tratamento; SmTGR; HQSAR; CoMFA; CoMSIA; Planejamento de fármacos; Schistosomiasis; Treatment; Drug design; CIENCIAS BIOLOGICAS::FARMACOLOGIA

Schistosomiasis is a neglected tropical disease (NTD) that affects many individuals, mainly in tropical areas. This disease is caused by blood flukes of the genus Schistosoma, which have the snails of the genus Biomphalaria as their intermediate hosts. The most used drug in schistosomiasis treatment is praziquantel, which because of its widespread use, brings concerns about the development of resistance. The enzyme Thioredoxin Glutathione Reductase of Schistosoma mansoni (SmTGR) has an important function in reactive oxygen species (ROS) detoxification, allowing the survival of parasites for a very long time in blood stream, protecting them against the host immune system. The dependence of the parasite on a single system for ROS detoxification, makes the SmTGR a promissing target in the development of new schistosomicidal drugs. Facing the need for development of new drugs against schistosomiasis, quantitative structure activity relationships (QSAR) studies were carried out for a series of oxadiazoles-2-oxides reported in literature as SmTGR inhibitors. Hologram-QSAR (HQSAR) analysis, a two-dimensional QSAR method (2D-QSAR), was performed. Furthermore comparative molecular field analysis (CoMFA) and comparative similarity indices analysis (CoMSIA), that are three-dimensional QSAR (3D-QSAR), were also carried out. In 3D-QSAR methods, two partial charge calculation methods were used: the empirical method Gasteiger-Hückel and the semiempirical method AM1-BCC. Two alignment strategies were also tested, one based on molecular volume superposition and the other based on a morphological similarity function. The QSAR models generated showed great robustness and external predictivity and can be used to predict the biological activity of new compounds inhibitors of SmTGR. The contribution and contour maps showed important structural information about oxadiazoles-2-oxides that was used for the design of new SmTGR inhibitors.