Search of Allosteric Inhibitors and Associated Proteins of an AKT-like Kinase from Trypanosoma cruzi

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 <i>Trypanosoma cruzi</i>. Here, we performed a virtual screening approach to find candidates that can bind regions on or near the Pleckstrin homology domain of an AKT-<i>like</i> protein in <i>T. cruzi.</i> 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-<i>like</i> kinase of the parasite; among them, a derivative of the pyrazolopyridine nucleus with an IC₅₀ of 14.25 ± 1.00 μM against amastigotes of <i>T. cruzi</i>. In addition, we built a protein⁻protein interaction network of <i>T. cruzi</i> to understand the role of the AKT-<i>like</i> 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 <i>T. cruzi</i>.