Identification of cisapride as new inhibitor of putrescine uptake in Trypanosoma cruzi by combined ligand- and structure-based virtual screening

European Journal of Medicinal Chemistry
R C DietrichL Gavernet

Abstract

Nowadays, the pharmacological therapy for the treatment of Chagas disease is based on two old drugs, benznidazole and nifurtimox, which have restricted efficacy against the chronic phase of the illness. To overcome the lack of efficacy of the traditional drugs (and their considerable toxicity), new molecular targets have been studied as starting points to the discovery of new antichagasic compounds. Among them, polyamine transporter TcPAT12 (also known as TcPOT1.1) represents an interesting macromolecule, since polyamines are essential for Trypanosoma cruzi, the parasite that causes the illness, but it cannot synthesize them de novo. In this investigation we report the results of a combined ligand- and structure-based virtual screening for the discovery of new inhibitors of TcPAT12. Initially we filtered out ZINC and Drugbank databases with similarity and QSAR models and then we submitted the candidates to a validated docking based screening. Four structures were selected and tested in T. cruzi epimastigotes proliferation and two of them, Cisapride and [2-(cyclopentyloxy)phenyl]methanamine showed inhibitory effects. Additionally, we performed transport assays which demonstrated that Cisapride interferes with putrescine uptake i...Continue Reading

Citations

Feb 13, 2020·Parasitology·Claudio A PereiraEdward Valera-Vera
Jun 12, 2018·Frontiers in Cellular and Infection Microbiology·Lucas N AlbercaAlan Talevi
Sep 28, 2018·Current Medicinal Chemistry·Alan TaleviMarcelo Comini

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