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Molecules 2017, 22(6), 1015;

Repositioning FDA Drugs as Potential Cruzain Inhibitors from Trypanosoma cruzi: Virtual Screening, In Vitro and In Vivo Studies

Unidad Académica Multidisciplinaria Reynosa-Rodhe, Universidad Autónoma de Tamaulipas, Carr. Reynosa-San Fernando, s/n, Reynosa 88779, México
Unidad de Investigación Biomédica de Zacatecas, Instituto Mexicano del Seguro Social (IMSS), Alameda Trinidad García de la Cadena, s/n, Zacatecas 98000, México
Departamento de Parasitología, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Prolongación de Carpio y Plan de Ayala, s/n, Ciudad de México 11340, México
Laboratory of Pharmaceutical Biothecnology, Centro de Biotecnología Genómica, Instituto Politécnico Nacional, Boulevard del Maestro, s/n, Esq. Elías Piña, Reynosa 88710, México
Author to whom correspondence should be addressed.
Academic Editors: Diego Muñoz-Torrero and Kelly Chibale
Received: 22 May 2017 / Revised: 14 June 2017 / Accepted: 15 June 2017 / Published: 18 June 2017
(This article belongs to the Special Issue Emerging Drug Discovery Approaches against Infectious Diseases)
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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 A computer-guided drug repositioning method was applied to identify potential FDA drugs (approved and withdrawn) as cruzain (Cz) inhibitors and trypanocidal effects were confirmed by in vitro and in vivo studies. 3180 FDA drugs were virtually screened using a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. View Full-Text
Keywords: drug repositioning; Trypanosoma cruzi; docking; cruzain; FDA drugs drug repositioning; Trypanosoma cruzi; docking; cruzain; FDA drugs

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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).

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Palos, I.; Lara-Ramirez, E.E.; Lopez-Cedillo, J.C.; Garcia-Perez, C.; Kashif, M.; Bocanegra-Garcia, V.; Nogueda-Torres, B.; Rivera, G. Repositioning FDA Drugs as Potential Cruzain Inhibitors from Trypanosoma cruzi: Virtual Screening, In Vitro and In Vivo Studies. Molecules 2017, 22, 1015.

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