Fuente: Molecules - Revista científica (MDPI) Molecules, Vol. 31, Pages 1139: An In Silico and In Vitro Approach Identified Potential Trypanothione Synthetase Inhibitors with Trypanocidal Activity
Molecules doi: 10.3390/molecules31071139
Authors:
Rogelio Gómez-Escobedo
Domingo Méndez-Álvarez
Alma D. Paz-González
Eyra Ortiz-Pérez
Lenci K. Vázquez-Jiménez
Ana Verónica Martínez-Vázquez
Timoteo Delgado-Maldonado
José M. Quintero-Solano
Citlali Vázquez
Emma Saavedra
Guadalupe Avalos-Navarro
Karina Vázquez
Gildardo Rivera
Benjamín Nogueda-Torres

In this study, a drug repurposing strategy was implemented with the aim of identifying new trypanocidal agents against Trypanosoma cruzi (T. cruzi). A total of 924 Food and Drug Administration (FDA)-approved drugs were screened by molecular docking on three sites of trypanothione synthetase (TS), including the catalytic site, a blind docking site, and a potential allosteric site. Selected compounds were further evaluated through in vitro and in vivo assays. Tadalafil, Zafirlukast, Raltegravir, and Olmesartan had better trypanocidal activity than the reference drugs Benznidazole and Nifurtimox in the in vitro evaluation against the trypomastigote form. Additionally, these drugs were able to decrease parasitemia by 20–50% in mice in an acute treatment. Molecular dynamics simulations (MDS) at 120 ns helped link findings from in vitro/in vivo experiments to a potential mechanism of action targeting T. cruzi trypanothione synthetase (TcTS). Therefore, the results encourage the use of these drugs to develop new anti-T. cruzi agents.