Abstract：
Alzheimer\'s disease (AD) is the leading cause of dementia in older adults. Drug repositioning is a process of finding new therapeutic applications for existing drugs. One of the methods in drug repositioning is to use the side-effect profile of a drug to identify a new therapeutic indication. The drugs with similar side-effects may act on similar biological targets and could affect the same biochemical process. In this study, we explored the Food and Drug Administration-approved drugs using PROMISCUOUS database to find those that have adverse effects profile comparable with the ligands being studied or used to treat AD. Here, we found that the ropinirole, a dopamine receptor agonist, shared a maximum number of side-effects with the drugs proven beneficial for treating AD. Furthermore, molecular modelling demonstrated that ropinirole exhibited strong binding affinity (-9.313 kcal/mol) and best ligand efficiency (0.49) with sigma-1 receptor. Here, we observed that the quaternary amino group of ropinirole is essential for binding with sigma-1 receptor. Molecular dynamic simulation indicated that the movement of the carboxy-terminal helices (α4/α5) could play a major role in the receptor\'s physiological functions. The neurotoxicity induced by Aβ25-35 in SH-SY5Y cells was reduced by ropinirole at concentrations 10, 30, and 50 µM. The effect on spatial learning and memory was examined in mice with Aβ25-35 induced memory deficit using the radial arm maze. Ropinirole (10 and 20 mg/kg) significantly improved the short and long-term memories in the radial arm maze test. Our results suggest that ropinirole has the potential to be repositioned for AD treatment.Communicated by Ramaswamy H. Sarma.
摘要：
阿尔茨海默病(AD)是导致老年人痴呆的主要原因。药物重新定位是为现有药物寻找新的治疗应用的过程。药物重新定位的方法之一是使用药物的副作用特征来识别新的治疗适应症。具有相似副作用的药物可能作用于相似的生物靶标，并可能影响相同的生化过程。在这项研究中,我们使用PROMISAUOUS数据库探索了食品和药物管理局批准的药物,以发现与正在研究或用于治疗AD的配体具有可比性的不良反应.这里,我们发现罗匹尼罗,多巴胺受体激动剂,与被证明对治疗AD有益的药物共享最大数量的副作用。此外，分子模型表明，罗匹尼罗与sigma-1受体表现出强结合亲和力（-9.313kcal/mol）和最佳配体效率（0.49）。这里,我们观察到罗匹尼罗的季氨基对于与sigma-1受体结合至关重要。分子动力学模拟表明，羧基末端螺旋（α4/α5）的运动可能在受体的生理功能中起主要作用。Aβ25-35在SH-SY5Y细胞中诱导的神经毒性被罗匹尼罗在浓度为10、30和50µM时降低。使用放射状臂迷宫在具有Aβ25-35诱导的记忆缺陷的小鼠中检查对空间学习和记忆的影响。Ropinirole（10和20mg/kg）显着改善了radial臂迷宫测试中的短期和长期记忆。我们的结果表明罗匹尼罗有可能被重新定位用于AD治疗。由RamaswamyH.Sarma沟通。
