Mohamed Tarek, Shakeri Arash, Rao Praveen P N
School of Pharmacy, Health Sciences Campus, University of Waterloo, 200 University Avenue West, Waterloo, Ontario N2L 3G1, Canada; Department of Chemistry, University of Waterloo, 200 University Avenue West, Waterloo, Ontario N2L 3G1, Canada.
School of Pharmacy, Health Sciences Campus, University of Waterloo, 200 University Avenue West, Waterloo, Ontario N2L 3G1, Canada.
Eur J Med Chem. 2016 May 4;113:258-72. doi: 10.1016/j.ejmech.2016.02.049. Epub 2016 Feb 22.
Alzheimer's disease is of major concern all over the world due to a number of factors including (i) an aging population (ii) increasing life span and (iii) lack of effective pharmacotherapy options. The past decade has seen intense research in discovering disease-modifying multitargeting small molecules as therapeutic options. The pathophysiology of Alzheimer's disease is attributed to a number of factors such as the cholinergic dysfunction, amyloid/tau toxicity and oxidative stress/mitochondrial dysfunction. In recent years, targeting the amyloid cascade has emerged as an attractive strategy to discover novel neurotherapeutics. Formation of beta-amyloid species, with different degrees of solubility and neurotoxicity is associated with the gradual decline in cognition leading to dementia. The two commonly used approaches to prevent beta-amyloid accumulation in the brain include (i) development of beta-secretase inhibitors and (ii) designing direct inhibitors of beta-amyloid (self-induced) aggregation. This review highlights the amyloid cascade hypothesis and the key chemical features required to design small molecules that inhibit lower and higher order beta-amyloid aggregates. Several recent examples of small synthetic molecules with disease-modifying properties were considered and their molecular docking studies were conducted using either a dimer or steric-zipper assembly of beta-amyloid. These investigations provide a mechanistic understanding on the structural requirements needed to design novel small molecules with anti-amyloid aggregation properties. Significantly, this work also demonstrates that the structural requirements to prevent aggregation of various amyloid species differs considerably, which explains the fact that many small molecules do not exhibit similar inhibition profile toward diverse amyloid species such as dimers, trimers, tetramers, oligomers, protofibrils and fibrils.
由于多种因素，包括（i）人口老龄化、（ii）寿命延长以及（iii）缺乏有效的药物治疗选择，阿尔茨海默病已成为全球主要关注的问题。在过去十年中，人们对发现具有疾病修饰作用的多靶点小分子作为治疗选择进行了深入研究。阿尔茨海默病的病理生理学归因于多种因素，如胆碱能功能障碍、淀粉样蛋白/ tau毒性以及氧化应激/线粒体功能障碍。近年来，针对淀粉样蛋白级联反应已成为发现新型神经治疗药物的一种有吸引力的策略。具有不同溶解度和神经毒性程度的β -淀粉样蛋白物种的形成与认知功能逐渐下降导致痴呆有关。预防β -淀粉样蛋白在大脑中积累的两种常用方法包括（i）开发β -分泌酶抑制剂和（ii）设计β -淀粉样蛋白（自身诱导）聚集的直接抑制剂。本综述强调了淀粉样蛋白级联反应假说以及设计抑制低阶和高阶β -淀粉样蛋白聚集体的小分子所需的关键化学特征。考虑了几个具有疾病修饰特性的小合成分子的近期实例，并使用β -淀粉样蛋白的二聚体或空间拉链组装体对其进行了分子对接研究。这些研究为设计具有抗淀粉样蛋白聚集特性的新型小分子所需的结构要求提供了机理理解。值得注意的是，这项工作还表明，预防各种淀粉样蛋白物种聚集的结构要求有很大差异，这解释了许多小分子对不同淀粉样蛋白物种（如二聚体、三聚体、四聚体、寡聚体、原纤维和纤维）没有表现出相似抑制谱的事实。
