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

Molecules

Jesús Oria-Hernández¹  Adriana Castillo-Villanueva¹  Erick Sierra-Campos²  Mónica Valdez-Solana²  Alejandra Vázquez-Raygoza³  Claudia Avitia-Domínguez³  Alfredo Téllez-Valencia³  Rafael Castillo⁴  Francisco Hernández-Luis⁴  Lucia Cano-González⁴  Israel Velázquez-Martínez⁴  Pedro Josué Trejo-Soto⁴  Alicia Hernández-Campos⁴ 

[1] Biochemistry and Genetics Laboratory, National Institute of Pediatrics, Ministry of Health, Mexico City 04534, Mexico;Faculty of Chemical Sciences, Juarez University of Durango State, Av. Artículo 123 S/N Fracc. Filadelfia, Gomez Palacio, Durango 35010, Mexico;Faculty of Medicine and Nutrition, Juarez University of Durango State, Av. Universidad y Fanny Anitua S/N, Durango 34000, Mexico;School of Chemistry, Pharmacy Department, National Autonomous University of Mexico, Mexico City 04510, Mexico;

关键词: human African trypanosomiasis;    triosephosphate isomerase;    enzymatic kinetics;    molecular dynamics simulation;   

DOI  :  10.3390/molecules22122055

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown