Repositioning FDA drugs as potential cruzain inhibitors from Trypanosoma cruzi: Virtual screening, in vitro and in vivo studies

Isidro Palos, Edgar E. Lara-Ramirez, Julio Cesar Lopez-Cedillo, Carlos Garcia-Perez, Muhammad Kashif, Virgilio Bocanegra-Garcia, Benjamin Nogueda-Torres, Gildardo Rivera

Research output: Contribution to journalArticlepeer-review

35 Scopus citations

Abstract

Chagas disease (CD) is a neglected disease caused by the parasite Trypanosoma cruzi, which affects underdeveloped countries. The current drugs of choice are nifurtimox and benznidazole, but both have severe adverse effects and less effectivity in chronic infections; therefore, the need to discover new drugs is essential. A computer-guided drug repositioning method was applied to identify potential FDA drugs (approved and withdrawn) as cruzain (Cz) inhibitors and trypanocidal effects were confirmed by in vitro and in vivo studies. 3180 FDA drugs were virtually screened using a structure-based approach. From a first molecular docking analysis, a set of 33 compounds with the best binding energies were selected. Subsequent consensus affinity binding, ligand amino acid contact clustering analysis, and ranked position were used to choose four known pharmacological compounds to be tested in vitro. Mouse blood samples infected with trypomastigotes from INC-5 and NINOA strains were used to test the trypanocidal effect of four selected compounds. Among these drugs, one fibrate antilipemic (etofyllin clofibrate) and three β-lactam antibiotics (piperacillin, cefoperazone, and flucloxacillin) showed better trypanocidal effects (LC50 range 15.8–26.1 µg/mL) in comparison with benznidazole and nifurtimox (LC50 range 33.1–46.7 µg/mL). A short-term in vivo evaluation of these compounds showed a reduction of parasitemia in infected mice (range 90–60%) at 6 h, but this was low compared to benznidazole (50%). This work suggests that four known FDA drugs could be used to design and obtain new trypanocidal agents.

Original languageEnglish
Article number1015
JournalMolecules
Volume22
Issue number6
DOIs
StatePublished - Jun 2017

Keywords

  • Cruzain
  • Docking
  • Drug repositioning
  • FDA drugs
  • Trypanosoma cruzi

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