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Molecules 2017, 22(12), 2055; doi:10.3390/molecules22122055

Species-Specific Inactivation of Triosephosphate Isomerase from Trypanosoma brucei: Kinetic and Molecular Dynamics Studies

1
Faculty of Medicine and Nutrition, Juarez University of Durango State, Av. Universidad y Fanny Anitua S/N, Durango 34000, Mexico
2
School of Chemistry, Pharmacy Department, National Autonomous University of Mexico, Mexico City 04510, Mexico
3
Biochemistry and Genetics Laboratory, National Institute of Pediatrics, Ministry of Health, Mexico City 04534, Mexico
4
Faculty of Chemical Sciences, Juarez University of Durango State, Av. Artículo 123 S/N Fracc. Filadelfia, Gomez Palacio, Durango 35010, Mexico
*
Author to whom correspondence should be addressed.
Received: 7 November 2017 / Revised: 19 November 2017 / Accepted: 21 November 2017 / Published: 24 November 2017
(This article belongs to the Special Issue Emerging Drug Discovery Approaches against Infectious Diseases)
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Abstract

Human African Trypanosomiasis (HAT), a disease that provokes 2184 new cases a year in Sub-Saharan Africa, is caused by Trypanosoma brucei. Current treatments are limited, highly toxic, and parasite strains resistant to them are emerging. Therefore, there is an urgency to find new drugs against HAT. In this context, T. brucei depends on glycolysis as the unique source for ATP supply; therefore, the enzyme triosephosphate isomerase (TIM) is an attractive target for drug design. In the present work, three new benzimidazole derivatives were found as TbTIM inactivators (compounds 1, 2 and 3) with an I50 value of 84, 82 and 73 µM, respectively. Kinetic analyses indicated that the three molecules were selective when tested against human TIM (HsTIM) activity. Additionally, to study their binding mode in TbTIM, we performed a 100 ns molecular dynamics simulation of TbTIM-inactivator complexes. Simulations showed that the binding of compounds disturbs the structure of the protein, affecting the conformations of important domains such as loop 6 and loop 8. In addition, the physicochemical and drug-like parameters showed by the three compounds suggest a good oral absorption. In conclusion, these molecules will serve as a guide to design more potent inactivators that could be used to obtain new drugs against HAT. View Full-Text
Keywords: human African trypanosomiasis; triosephosphate isomerase; enzymatic kinetics; molecular dynamics simulation human African trypanosomiasis; triosephosphate isomerase; enzymatic kinetics; molecular dynamics simulation
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MDPI and ACS Style

Vázquez-Raygoza, A.; Cano-González, L.; Velázquez-Martínez, I.; Trejo-Soto, P.J.; Castillo, R.; Hernández-Campos, A.; Hernández-Luis, F.; Oria-Hernández, J.; Castillo-Villanueva, A.; Avitia-Domínguez, C.; Sierra-Campos, E.; Valdez-Solana, M.; Téllez-Valencia, A. Species-Specific Inactivation of Triosephosphate Isomerase from Trypanosoma brucei: Kinetic and Molecular Dynamics Studies. Molecules 2017, 22, 2055.

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