Abstract
Proteins associated to the PI3K/AKT/mTOR signaling pathway are widely used targets for cancer treatment, and in recent years they have also been evaluated as putative targets in trypanosomatids parasites, such as Trypanosoma cruzi. Here, we performed a virtual screening approach to find candidates that can bind regions on or near the Pleckstrin homology domain of an AKT-like protein in T. cruzi. The compounds were also evaluated in vitro. The in silico and experimental results allowed us to identify a set of compounds that can potentially alter the intracellular signaling pathway through the AKT-like kinase of the parasite; among them, a derivative of the pyrazolopyridine nucleus with an IC50 of 14.25 ± 1.00 μM against amastigotes of T. cruzi. In addition, we built a protein–protein interaction network of T. cruzi to understand the role of the AKT-like protein in the parasite, and look for additional proteins that can be postulated as possible novel molecular targets for the rational design of compounds against T. cruzi.
Highlights
Around 40,000 new cases of people with Chagas disease are reported
The model obtained for the TcAKT-like protein showed conserved structural folding between protein kinases
It contains the Pleckstrin homology domain (PH) domain, which has a length of 99 amino acids, from Ser2 to Pro100 (Figure 1A)
Summary
Around 40,000 new cases of people with Chagas disease are reported. This pathology is caused by a flagellated protozoan called Trypanosoma cruzi, which is transmitted to humans through a triatomine insect that functions as its vector. This parasite has two obligatory phases in the host, a replicative intracellular form called amastigote and a non-reproductive blood form called trypomastigote. Some of the effects of Chagas disease are alterations in the immune response, cardiomyopathy, and gastrointestinal disease. It is necessary to search for new, effective, and safe pharmacological alternatives against Chagas disease
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