Tran Phuong-Thao, Hoang Van-Hai, Lee Jeewoo, Hien Tran Thi Thu, Tung Nguyen Thanh, Ngo Son Tung
Department of Pharmaceutical Chemistry, Hanoi University of Pharmacy Hanoi Vietnam
Institute of Research and Development, Duy Tan University Da Nang 550000 Vietnam.
RSC Adv. 2019 Sep 19;9(51):29619-29627. doi: 10.1039/c9ra05763c. eCollection 2019 Sep 18.
Alzheimer's disease (AD) is the most common form of neurodegenerative disease currently. It is widely accepted that AD is characterized by the self-assembly of amyloid beta (Aβ) peptides. The human glutaminyl cyclase (hQC) enzyme is characterized by association with Aβ peptide generation. The development of hQC inhibitors could prevent the self-aggregation of Aβ peptides, resulting in impeding AD. Utilizing structural knowledge of the hQC substrates and known hQC inhibitors, new heterocyclic and peptidomimetic derivatives were synthesized and were able to inhibit the hQC enzyme. The inhibiting abilities of these compounds were evaluated using a fluorometric assay. The binding mechanism at the atomic level was estimated using molecular docking, free energy perturbation, and quantum chemical calculation methods. The predicted log(BBB) and human intestinal absorption values indicated that these compounds are able to permeate the blood-brain barrier and be well-absorbed through the gastrointestinal tract. Overall, 5,6-dimethoxy--(3-(5-methyl-1-imidazol-1-yl)propyl)-1-benzo[]imidazol-2-amine (1_2) was indicated as a potential drug for AD treatment.
阿尔茨海默病（AD）是目前最常见的神经退行性疾病形式。人们普遍认为，AD的特征是β-淀粉样蛋白（Aβ）肽的自组装。人谷氨酰胺环化酶（hQC）的特点是与Aβ肽的产生有关。hQC抑制剂的开发可以防止Aβ肽的自聚集，从而延缓AD的发展。利用hQC底物和已知hQC抑制剂的结构知识，合成了新的杂环和拟肽衍生物，它们能够抑制hQC酶。使用荧光测定法评估了这些化合物的抑制能力。使用分子对接、自由能扰动和量子化学计算方法估计了原子水平上的结合机制。预测的log(BBB)和人体肠道吸收值表明，这些化合物能够穿透血脑屏障并通过胃肠道被良好吸收。总体而言，5,6-二甲氧基-（3-（5-甲基-1-咪唑-1-基）丙基）-1-苯并咪唑-2-胺（1_2）被认为是一种潜在的AD治疗药物。
