Dell 050010, Colombia; [email protected] (R.O.); [email protected] (M.M.V.); [email protected] (S.M.R.) GEPAMOL, Centro de Investigaciones Biom

Dell 050010, Colombia; [email protected] (R.O.); [email protected] (M.M.V.); [email protected] (S.M.R.) GEPAMOL, Centro de Investigaciones Biom icas, Universidad del Quind , Armenia 630004, Colombia; Esfenvalerate Description [email protected] QUIBIO, Facultad de Ciencias B icas, Universidad Santiago de Cali, Cali 760035, Colombia Correspondence: [email protected] These authors contributed equally to this operate.Received: 2 November 2018; Accepted: 17 November 2018; Published: eight DecemberAbstract: Proteins connected towards the PI3KAKTmTOR signaling pathway are extensively applied targets for cancer therapy, and in recent years they’ve also been evaluated as putative targets in trypanosomatids parasites, which include Trypanosoma cruzi. Right here, we performed a virtual screening method to locate candidates that can bind regions on or close to the Pleckstrin homology domain of an AKTlike protein in T. cruzi. The compounds have been also evaluated in vitro. The in silico and experimental results allowed us to identify a set of compounds that will potentially alter the intracellular signaling pathway through the AKTlike kinase from the parasite; amongst them, a derivative on the pyrazolopyridine nucleus with an IC50 of 14.25 1.00 against amastigotes of T. cruzi. Furthermore, we built a protein rotein interaction network of T. cruzi to know the part of the AKTlike protein within the parasite, and appear for additional proteins that can be postulated as possible novel molecular targets for the rational design of compounds against T. cruzi. Search phrases: Trypanosoma cruzi; protein kinase B; pleckstrin homology domain; drug discovery1. Introduction Annually, around 40,000 new cases of individuals with Chagas disease are reported. This pathology is caused by a flagellated protozoan named Trypanosoma cruzi, which is transmitted to humans by means of a Ace 2 Inhibitors medchemexpress triatomine insect that functions as its vector. This parasite has two obligatory phases inside the host, a replicative intracellular form called amastigote in addition to a nonreproductive blood type named trypomastigote. Several of the effects of Chagas illness are alterations inside the immune response, cardiomyopathy, and gastrointestinal illness. Two antiparasitic drugs, nifurtimox and benznidazole are employed for therapy, but these have shown deficiencies associated to their toxicity and low effectiveness within the chronic phase, also as reported circumstances of drug resistance [1]. Thus, it can be essential to search for new, successful, and safe pharmacological options against Chagas illness. A single strategy to style novel inhibitors is by means of the identification of novel molecular targets. One example is, a subgroup of SerThr kinases proteins called AGC kinases has been described as vital for the regulation, development, survival, differentiation, metabolism, and proliferation of cells. The protein kinase B (PKB or AKT) is a part of this group [4,5]. You will find various studies from the inhibition of PKB proteins and these present within the PI3KAKTmTOR signaling pathway, so as to manage malignantInt. J. Mol. Sci. 2018, 19, 3951; doi:ten.3390ijms19123951 www.mdpi.comjournalijmsInt. J. Mol. Sci. 2018, 19,2 ofcells and uncover superior therapeutic options for different forms of cancer [6]. Some proteins from the PI3KAKTmTOR pathway are also studied for the handle of some parasitic pathology. Recently, we reported our studies of recognition and inhibition of the LdRACAKTlike protein in Leishmania panamensis, suggesting that the AKTlike protein in Leishmania spp.