一劳永逸？用一种药物击中多个阿尔茨海默病靶点,Frontiers in Neuroscience

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一劳永逸？用一种药物击中多个阿尔茨海默病靶点
Frontiers in Neuroscience ( IF 3.2 ) Pub Date : 2016-04-25 , DOI: 10.3389/fnins.2016.00177
Rebecca E Hughes ₁ , Katarina Nikolic ₂ , Rona R Ramsay ₁

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亮点正在探索用于多靶点药物设计的许多 AD 靶点组合。新的数据库和模型增加了计算药物设计的潜力利拉鲁肽和其他抗糖尿病药物是重新用于 AD 的有力候选者。Donecopride 是一种双 5-HT/AChE 抑制剂，在临床前研究中显示出前景阿尔茨海默病是一种复杂的多因素疾病，其机制仍未完全了解。随着对疾病进展的新见解的发现，必须设计新药以针对导致神经元损伤的疾病方面，而不仅仅是目前由单一靶点药物解决的症状。使用多靶点药物 (MTD) 同时针对疾病病理学的多个方面变得可能。旨在作为非专家的介绍，这篇综述描述了关键的 MTD 设计方法，即基于结构的、计算机模拟和数据挖掘，以评估是什么阻止了化合物从临床进入市场。利用脱靶效应重新利用现有药物可降低开发成本、上市时间以及与安全性和药代动力学相关的不确定性。目前正在研究用于重新治疗阿尔茨海默病的最有希望的药物是雷沙吉兰，最初开发用于治疗帕金森病，以及利拉鲁肽，一种抗糖尿病药。合理的药物设计可以结合多种药物的药效团，系统地改变功能基团，并通过虚拟筛选对它们进行排序。实验证实的命中被合理地修改以产生有效的多效先导化合物。这种方法的例子是具有类似于雷沙吉兰的特性的 ASS234 和多奈必利，一种乙酰胆碱酯酶抑制剂和具有促认知作用的 5-HT4 受体激动剂的混合物。利用这些跨学科的方法，公私合作的主导工厂承诺更快地将新药交付给诊所。

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One for All? Hitting Multiple Alzheimer's Disease Targets with One Drug

HIGHLIGHTS Many AD target combinations are being explored for multi-target drug design. New databases and models increase the potential of computational drug design Liraglutide and other antidiabetics are strong candidates for repurposing to AD. Donecopride a dual 5-HT/AChE inhibitor shows promise in pre-clinical studies Alzheimer's Disease is a complex and multifactorial disease for which the mechanism is still not fully understood. As new insights into disease progression are discovered, new drugs must be designed to target those aspects of the disease that cause neuronal damage rather than just the symptoms currently addressed by single target drugs. It is becoming possible to target several aspects of the disease pathology at once using multi-target drugs (MTDs). Intended as an introduction for non-experts, this review describes the key MTD design approaches, namely structure-based, in silico, and data-mining, to evaluate what is preventing compounds progressing through the clinic to the market. Repurposing current drugs using their off-target effects reduces the cost of development, time to launch, and the uncertainty associated with safety and pharmacokinetics. The most promising drugs currently being investigated for repurposing to Alzheimer's Disease are rasagiline, originally developed for the treatment of Parkinson's Disease, and liraglutide, an antidiabetic. Rational drug design can combine pharmacophores of multiple drugs, systematically change functional groups, and rank them by virtual screening. Hits confirmed experimentally are rationally modified to generate an effective multi-potent lead compound. Examples from this approach are ASS234 with properties similar to rasagiline, and donecopride, a hybrid of an acetylcholinesterase inhibitor and a 5-HT4 receptor agonist with pro-cognitive effects. Exploiting these interdisciplinary approaches, public-private collaborative lead factories promise faster delivery of new drugs to the clinic.

更新日期：2016-04-25

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