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Open AccessArticle

Repositioned Drugs for Chagas Disease Unveiled via Structure-Based Drug Repositioning

Biotechnology Center (BIOTEC), Technische Universität Dresden, 01307 Dresden, Germany
Facultad de Ciencias Químicas, Universidad Autónoma Benito Juárez, Oaxaca 68120, Mexico
Departamento de Parasitología, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Ciudad de México 11340, Mexico
Unidad de Investigación Médica en Enfermedades Infecciosas y Parasitarias, UMAE Hospital de Pediatría, Centro Médico Siglo XXI, Instituto Mexicano del Seguro Social, México City 06720, Mexico
Laboratorio de Investigación y Diagnóstico Molecular, Instituto de Ciencias Biológicas, Universidad de Ciencias y Artes de Chiapas. Libramiento Norte Poniente 1150, Col. Lajas Maciel, Tuxtla Gutiérrez 29029, Mexico
Laboratorio de Biotecnología Farmacéutica, Centro de Biotecnología Genómica, Instituto Politécnico Nacional, Reynosa 88710, Mexico
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2020, 21(22), 8809;
Received: 22 October 2020 / Revised: 8 November 2020 / Accepted: 16 November 2020 / Published: 20 November 2020
(This article belongs to the Section Molecular Informatics)
Chagas disease, caused by the parasite Trypanosoma cruzi, affects millions of people in South America. The current treatments are limited, have severe side effects, and are only partially effective. Drug repositioning, defined as finding new indications for already approved drugs, has the potential to provide new therapeutic options for Chagas. In this work, we conducted a structure-based drug repositioning approach with over 130,000 3D protein structures to identify drugs that bind therapeutic Chagas targets and thus represent potential new Chagas treatments. The screening yielded over 500 molecules as hits, out of which 38 drugs were prioritized following a rigorous filtering process. About half of the latter were already known to have trypanocidal activity, while the others are novel to Chagas disease. Three of the new drug candidates—ciprofloxacin, naproxen, and folic acid—showed a growth inhibitory activity in the micromolar range when tested ex vivo on T. cruzi trypomastigotes, validating the prediction. We show that our drug repositioning approach is able to pinpoint relevant drug candidates at a fraction of the time and cost of a conventional screening. Furthermore, our results demonstrate the power and potential of structure-based drug repositioning in the context of neglected tropical diseases where the pharmaceutical industry has little financial interest in the development of new drugs. View Full-Text
Keywords: Chagas; Trypanosoma cruzi; drug repositioning; structural screening; non-covalent interactions Chagas; Trypanosoma cruzi; drug repositioning; structural screening; non-covalent interactions
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Adasme, M.F.; Bolz, S.N.; Adelmann, L.; Salentin, S.; Haupt, V.J.; Moreno-Rodríguez, A.; Nogueda-Torres, B.; Castillo-Campos, V.; Yepez-Mulia, L.; De Fuentes-Vicente, J.A.; Rivera, G.; Schroeder, M. Repositioned Drugs for Chagas Disease Unveiled via Structure-Based Drug Repositioning. Int. J. Mol. Sci. 2020, 21, 8809.

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