Identificação de novos compostos bioativos contra tripanossomatídeos a partir de estratégias integradas em química medicinal

• Autor(a) principal: Melo Filho, Cleber Camilo de
• Data de Publicação: 2018
• Tipo de documento: Tese
• Idioma: por
• Título da fonte: Repositório Institucional da UFG
• Texto Completo: http://repositorio.bc.ufg.br/tede/handle/tede/9714
• topic: Triagem virtual; Descoberta de fármacos; Trypanosoma cruzi; Leishmania; Tratamento; Virtual screening; Drug discovery; Treatment; CIENCIAS BIOLOGICAS::PARASITOLOGIA

Trypanosomatids are parasites that cause different diseases affecting mainly low-income populations from countries in development or underdeveloped countries. These diseases are classified as neglected tropical diseases (NTDs). The few drugs available for the treatment of these parasitic diseases present several problems regarding low efficacy, resistance, and toxicity, making the need of new therapeutic options an urgent task. In this sense, the aim of this work was the identification of novel drug candidates against trypanosomatids through the application of integrated strategies in Medicinal Chemistry. To achieve this goal, three studies were performed combining different computer assisted drug design (CADD) approaches and experimental validation. In the first study, 39 virtual hits were identified by quantitative structure activity relationships (QSAR)-based virtual screening (VS) and selected for experimental evaluation. Among them, 13 compounds were active and selective in vitro against intracellular T. cruzi. Additionally, an in silico multi-parameter analysis for evaluation and comparison of some pharmacokinetic (ADMET) and physicochemical properties, with potency and selectivity, allowed the prioritization of the most promising compounds for further in vivo assays. In the second study, VS was performed for identification of novel potential inhibitors of pyruvate kinase (PK) from Leishmania spp., allowing the discovery of 14 novel potential inhibitors of this enzyme. These compounds were submitted to experimental evaluation against L. infantum amastigotes. In the third study, a dual-target VS was performed, allowing the identification of 15 potential inhibitors of both PK and sterol 14 α-demethylase (CYP51) of Leishmania spp., also predicted as active compounds against L. infantum amastigotes by QSAR models. Therefore, this work has demonstrated the potential of the integration of computational and experimental methods for the identification of active compounds against trypanosomatids.