School of Biomedical Engineering, Tianjin Medical University, Tianjin, China.
J Alzheimers Dis. 2024;101(4):1355-1366. doi: 10.3233/JAD-240235.
Alzheimer's disease (AD) is a neurodegenerative disorder that is the most common form of dementia in the elderly. The drugs currently used to treat AD only have limited effects and are not able to cure the disease. Drug repositioning has increasingly become a promising approach to find potential drugs for diseases like AD.
To screen potential drug candidates for AD based on the relationship between risk genes of AD and drugs.
We collected the risk genes of AD and retrieved the information of known drugs from DrugBank. Then, the AD-related genes and the targets of each drug were mapped to the human protein-protein interaction network (PPIN) to represent AD and the drugs on the network. The network distances between each drug and AD were calculated to screen the drugs proximal to AD-related genes on PPIN, and the screened drug candidates were further analyzed by molecular docking and molecular dynamics simulations.
We compiled a list of 714 genes associated with AD. From 5,833 drugs used for human diseases, we identified 1,044 drugs that could be potentially used to treat AD. Then, amyloid-β (Aβ) protein, the key molecule involved in the pathogenesis of AD was selected as the target to further screen drugs that may inhibit Aβ aggregation by molecular docking. We found that ergotamine and RAF-265 could bind stably with Aβ. In further analysis by molecular dynamics simulations, both drugs exhibited reasonable stability.
Our work indicated that ergotamine and RAF-265 may be potential candidates for treating AD.
阿尔茨海默病（AD）是一种神经退行性疾病，是老年人中最常见的痴呆症形式。目前用于治疗 AD 的药物仅具有有限的效果，并且无法治愈该疾病。药物重定位已越来越成为寻找 AD 等疾病潜在药物的一种有前途的方法。
基于 AD 的风险基因与药物之间的关系，筛选 AD 的潜在药物候选物。
我们收集了 AD 的风险基因，并从 DrugBank 中检索了已知药物的信息。然后，将 AD 相关基因和每种药物的靶标映射到人类蛋白质-蛋白质相互作用网络（PPIN）上，以代表 AD 和网络上的药物。计算每个药物与 AD 之间的网络距离，以筛选与 PPIN 上 AD 相关基因接近的药物，并通过分子对接和分子动力学模拟对筛选出的候选药物进行进一步分析。
我们编制了一份与 AD 相关的 714 个基因列表。从用于人类疾病的 5833 种药物中，我们确定了 1044 种可能用于治疗 AD 的药物。然后，选择淀粉样蛋白-β（Aβ）蛋白作为靶点，进一步筛选可能通过分子对接抑制 Aβ聚集的药物。我们发现麦角胺和 RAF-265 可以与 Aβ稳定结合。通过分子动力学模拟的进一步分析表明，这两种药物均表现出合理的稳定性。
我们的工作表明，麦角胺和 RAF-265 可能是治疗 AD 的潜在候选药物。
