TY - JOUR
T1 - Repositioning FDA drugs as potential cruzain inhibitors from Trypanosoma cruzi
T2 - Virtual screening, in vitro and in vivo studies
AU - Palos, Isidro
AU - Lara-Ramirez, Edgar E.
AU - Lopez-Cedillo, Julio Cesar
AU - Garcia-Perez, Carlos
AU - Kashif, Muhammad
AU - Bocanegra-Garcia, Virgilio
AU - Nogueda-Torres, Benjamin
AU - Rivera, Gildardo
N1 - Publisher Copyright:
© 2017 by the authors.
PY - 2017/6
Y1 - 2017/6
N2 - 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 A computer-guided drug repositioning method was applied to identify potential FDA drugs (approved and withdrawn) as cruzain (Cz) inhibitors and trypanocidal effects were confirmed by in vitro and in vivo studies. 3180 FDA drugs were virtually screened using a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.
AB - 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 A computer-guided drug repositioning method was applied to identify potential FDA drugs (approved and withdrawn) as cruzain (Cz) inhibitors and trypanocidal effects were confirmed by in vitro and in vivo studies. 3180 FDA drugs were virtually screened using a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.
KW - Cruzain
KW - Docking
KW - Drug repositioning
KW - FDA drugs
KW - Trypanosoma cruzi
UR - http://www.scopus.com/inward/record.url?scp=85021229825&partnerID=8YFLogxK
U2 - 10.3390/molecules22061015
DO - 10.3390/molecules22061015
M3 - Artículo
C2 - 28629155
SN - 1420-3049
VL - 22
JO - Molecules
JF - Molecules
IS - 6
M1 - 1015
ER -