Discovery of novel Trypanosoma cruzi glyceraldehyde-3-phosphate dehydrogenase inhibitors

Based on its essential role in the life cycle of Trypanosoma cruzi, the glycolytic enzyme glyceraldehyde 3-phosphate dehydrogenase (GAPDH) has been considered a promising target for the development of novel chemotherapeutic agents for the treatment of Chagas’ disease. In the course of our research program to discover novel inhibitors of this trypanosomatid enzyme, we have explored a combination of structure and ligand-based virtual screening techniques as a complementary approach to a biochemical screening of natural products using a standard biochemical assay. Seven natural products, including anacardic acids, flavonoid derivatives, and one glucosylxanthone were identified as novel inhibitors of T. cruzi GAPDH. Promiscuous inhibition induced by nonspecific aggregation has been discarded as specific inhibition was not reversed or affected in all cases in the presence of Triton X-100, demonstrating the ability of the assay to find authentic inhibitors of the enzyme. The structural diversity of this series of promising natural products is of special interest in drug design, and should therefore be useful in future medicinal chemistry efforts aimed at the development of new GAPDH inhibitors having increased potency.

Virtual screening strategies can be very attractive in the discovery and development of new drugs for neglected diseases. As part of our ongoing efforts to find novel potential inhibitors of Trypanosoma cruzi GAPDH aimed at treating Chagas´disease, we have used a combination of ligand-based and structure-based techniques to screen an in-house natural product database in a sequential manner. In an information overloaded chemical space, the use of techniques from complementary approaches resulted in the identification of seven bioactive natural products that include anacardic acids, flavonoid derivatives and one glucosylxanthone.Figure optionsDownload as PowerPoint slide