Chagas' disease is a major cause of morbidity and mortality in Latin America. The limited drugs available for the treatment of this parasitic disease have severe limitations, including poor efficacy and high toxicity. The enzyme cruzain, the major cysteine protease from Trypanosoma cruzi, is an attractive target for the development of a new generation of trypanocidal agents. In order to search for novel classes of cruzain inhibitors, structure-based virtual screening (SBVS) approaches were employed considering two subsets of componds (lead- and fragment-like) from ZINC. Initially, the compounds were screened with the program DOCK, and the top hits from each subset were subsequently evaluated by the GOLD and Surflex methods. A number of computational hits was inspected and selected among the best ranked molecules from each docking strategy. The biochemical evaluation of 18 compounds possessing substantial structural diversity against recombinant T. cruzi cruzain allowed the identification of a potent (IC50 = 580 nM, Ki = 100 nM) and non-covalent inhibitor (LE = 0.53 kcal mol-1 per non-H atom), which was also active against T. cruzi whole cell cultures. These results provide a promising starting point for lead optimization efforts. The detailed results and in vitro anti-T. cruzi properties of these compounds will be presented.

Virtual screening strategies for the discovery of new inhibitors of cruzain from <i>Trypanosoma cruzi</i><i> </i>

248th National Meeting (2014)

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Virtual screening strategies for the discovery of new inhibitors of cruzain from Trypanosoma cruzi