阿尔茨海默病的多靶点药物设计策略：聚焦胆碱能传递与淀粉样β蛋白聚集
Multitarget drug design strategy in Alzheimer's disease: focus on cholinergic transmission and amyloid-β aggregation.
作者信息
Simoni Elena, Bartolini Manuela, Abu Izuddin F, Blockley Alix, Gotti Cecilia, Bottegoni Giovanni, Caporaso Roberta, Bergamini Christian, Andrisano Vincenza, Cavalli Andrea, Mellor Ian R, Minarini Anna, Rosini Michela
机构信息
Department of Pharmacy & Biotechnology, Alma Mater Studiorum-University of Bologna, Via Belmeloro 6, 40126 Bologna, Italy.
School of Life Sciences, University of Nottingham, University Park, Nottingham, NG7 2RD, UK.
出版信息
Future Med Chem. 2017 Jun;9(10):953-963. doi: 10.4155/fmc-2017-0039. Epub 2017 Jun 20.
AIM
Alzheimer pathogenesis has been associated with a network of processes working simultaneously and synergistically. Over time, much interest has been focused on cholinergic transmission and its mutual interconnections with other active players of the disease. Besides the cholinesterase mainstay, the multifaceted interplay between nicotinic receptors and amyloid is actually considered to have a central role in neuroprotection. Thus, the multitarget drug-design strategy has emerged as a chance to face the disease network.
METHODS
By exploiting the multitarget approach, hybrid compounds have been synthesized and studied in vitro and in silico toward selected targets of the cholinergic and amyloidogenic pathways.
RESULTS
The new molecules were able to target the cholinergic system, by joining direct nicotinic receptor stimulation to acetylcholinesterase inhibition, and to inhibit amyloid-β aggregation.
CONCLUSION
The compounds emerged as a suitable starting point for a further optimization process.
目的
阿尔茨海默病的发病机制与一系列同时发生且协同作用的过程网络相关。随着时间的推移，人们的许多兴趣都集中在胆碱能传递及其与该疾病其他活跃因素的相互联系上。除了胆碱酯酶这个主要因素外，烟碱型受体与淀粉样蛋白之间多方面的相互作用实际上被认为在神经保护中起核心作用。因此，多靶点药物设计策略已成为应对疾病网络的一个契机。
方法
通过采用多靶点方法，已合成了杂合化合物，并针对胆碱能和淀粉样蛋白生成途径的选定靶点进行了体外和计算机模拟研究。
结果
这些新分子能够通过将直接烟碱型受体刺激与乙酰胆碱酯酶抑制相结合来靶向胆碱能系统，并抑制β-淀粉样蛋白聚集。
结论
这些化合物成为进一步优化过程的合适起点。
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