Academic Journal

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

التفاصيل البيبلوغرافية
العنوان: Species-Specific Inactivation of Triosephosphate Isomerase from Trypanosoma brucei: Kinetic and Molecular Dynamics Studies
المؤلفون: Alejandra Vázquez-Raygoza, Lucia Cano-González, Israel Velázquez-Martínez, Pedro Trejo-Soto, Rafael Castillo, Alicia Hernández-Campos, Francisco Hernández-Luis, Jesús Oria-Hernández, Adriana Castillo-Villanueva, Claudia Avitia-Domínguez, Erick Sierra-Campos, Mónica Valdez-Solana, Alfredo Téllez-Valencia
المصدر: Molecules; Volume 22; Issue 12; Pages: 2055
بيانات النشر: Multidisciplinary Digital Publishing Institute
سنة النشر: 2017
المجموعة: MDPI Open Access Publishing
مصطلحات موضوعية: human African trypanosomiasis, triosephosphate isomerase, enzymatic kinetics, molecular dynamics simulation
جغرافية الموضوع: agris
الوصف: 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.
نوع الوثيقة: text
وصف الملف: application/pdf
اللغة: English
Relation: Medicinal Chemistry; https://dx.doi.org/10.3390/molecules22122055
DOI: 10.3390/molecules22122055
الاتاحة: https://doi.org/10.3390/molecules22122055
Rights: https://creativecommons.org/licenses/by/4.0/
رقم الانضمام: edsbas.784F4CA6
قاعدة البيانات: BASE
الوصف
DOI:10.3390/molecules22122055