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
Molecules. 2017 Nov 24;22(12):2055. doi: 10.3390/molecules22122055.
Human African Trypanosomiasis (HAT), a disease that provokes 2184 new cases a year in Sub-Saharan Africa, is caused by . 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, 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 , and ) with an I 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.
人类非洲锥虫病（HAT）是一种在撒哈拉以南非洲地区每年引发 2184 例新病例的疾病，由 引起。目前的治疗方法有限，毒性很高，而且寄生虫株对它们的耐药性也在出现。因此，迫切需要寻找针对 HAT 的新药。在这种情况下， 依赖糖酵解作为唯一的 ATP 供应来源；因此，磷酸丙糖异构酶（TIM）是药物设计的一个有吸引力的靶标。在本工作中，发现了三种新的苯并咪唑衍生物作为 TbTIM 失活剂（化合物 、 和 ），其 I 值分别为 84、82 和 73µM。动力学分析表明，这三种分子在测试针对人 TIM（HsTIM）活性时具有选择性。此外，为了研究它们在 TbTIM 中的结合模式，我们对 TbTIM-失活剂复合物进行了 100 ns 的分子动力学模拟。模拟表明，化合物的结合扰乱了蛋白质的结构，影响了重要结构域的构象，如环 6 和环 8。此外，这三种化合物表现出的物理化学和类药性参数表明它们具有良好的口服吸收性。总之，这些分子将作为设计更有效的失活剂的指南，这些失活剂可用于获得针对 HAT 的新药。
