School of Biomedical Engineering, Tianjin Medical University, Tianjin, China.
CNS Neurosci Ther. 2023 Nov;29(11):3307-3321. doi: 10.1111/cns.14260. Epub 2023 May 14.
Alzheimer's disease (AD) and type 2 diabetes (T2D) are two of the most common diseases in elderly population and they have a high rate of comorbidity. Study has revealed that T2D is a major risk factor of AD, and thus exploring therapeutic approaches that can target both diseases has drawn much interest in recent years. In this study, we tried to explore drugs that could be potentially used to prevent or treat both AD and T2D via a drug repositioning approach.
We first searched the known drugs that may be effective to T2D treatment based on the network distance between the T2D-associated genes and drugs deposited in the DrugBank database. Then, via molecular docking, we further screened these drugs by examining their interaction with islet amyloid polypeptide (IAPP) and Aβ42 peptide, the key components involved in the pathogenesis of T2D or AD. Finally, the binding between the selected drug candidates and the target proteins was verified by molecular dynamics (MD) simulation; and the potential function of the drug candidates and the corresponding targets were analyzed.
From multiple resources, 734 T2D-associated genes were collected, and a list of 1109 drug candidates for T2D was obtained. We found that hypericin had the lowest binding energy and the most stable interaction with either IAPP or Aβ42 peptide. In addition, we also found that the target genes regulated by hypericin were differentially expressed in the tissues related to the two diseases.
Our results show that hypericin may be able to bind with IAPP and Aβ42 stably and prevent their accumulation, and thus could be a promising drug candidate for treating the comorbidity of AD and T2D.
阿尔茨海默病（AD）和 2 型糖尿病（T2D）是老年人群中最常见的两种疾病，它们的合并发病率很高。研究表明，T2D 是 AD 的一个主要危险因素，因此，近年来探索能够同时针对这两种疾病的治疗方法引起了广泛关注。在这项研究中，我们试图通过药物重定位方法探索可能用于预防或治疗 AD 和 T2D 的药物。
我们首先根据与糖尿病相关的基因与 DrugBank 数据库中药物的网络距离，搜索可能对 T2D 治疗有效的已知药物。然后，通过分子对接，我们进一步筛选了这些药物，考察了它们与胰岛淀粉样多肽（IAPP）和 Aβ42 肽的相互作用，IAPP 和 Aβ42 肽是参与 T2D 或 AD 发病机制的关键成分。最后，通过分子动力学（MD）模拟验证所选候选药物与靶蛋白的结合，并分析候选药物和相应靶标的潜在功能。
从多个资源中收集了 734 个与 T2D 相关的基因，并获得了 1109 种用于 T2D 的候选药物列表。我们发现金丝桃素与 IAPP 或 Aβ42 肽的结合能最低，相互作用最稳定。此外，我们还发现，金丝桃素调节的靶基因在与两种疾病相关的组织中表达差异。
我们的结果表明，金丝桃素可能能够与 IAPP 和 Aβ42 稳定结合，防止其积累，因此可能是治疗 AD 和 T2D 合并症的有前途的候选药物。
