School of Pharmacy, Monash University Malaysia, Jalan Lagoon Selatan, Bandar Sunway, 47500, Selangor Darul Ehsan, Malaysia; School of Pharmacy and Applied Science, La Trobe Institute for Molecular Sciences, La Trobe University, Edwards Rd., Bendigo, 3550, Australia.
School of Pharmacy and Applied Science, La Trobe Institute for Molecular Sciences, La Trobe University, Edwards Rd., Bendigo, 3550, Australia.
Biomed Pharmacother. 2018 Oct;106:553-565. doi: 10.1016/j.biopha.2018.06.147. Epub 2018 Jul 11.
An increase in dementia numbers and global trends in population aging across the world prompts the need for new medications to treat the complex biological dysfunctions, such as neurodegeneration associated with dementia. Alzheimer's disease (AD) is the most common form of dementia. Cholinergic signaling, which is important in cognition, is slowly lost in AD, so the first line therapy is to treat symptoms with acetylcholinesterase inhibitors to increase levels of acetylcholine. Out of five available FDA-approved AD medications, donepezil, galantamine and rivastigmine are cholinesterase inhibitors while memantine, a N-methyl d-aspartate (NMDA) receptor antagonist, blocks the effects of high glutamate levels. The fifth medication consists of a combination of donepezil and memantine. Although these medications can reduce and temporarily slow down the symptoms of AD, they cannot stop the damage to the brain from progressing. For a superior therapeutic effect, multi-target drugs are required. Thus, a Multi-Target-Directed Ligand (MTDL) strategy has received more attention by scientists who are attempting to develop hybrid molecules that simultaneously modulate multiple biological targets. This review highlights recent examples of the MTDL approach and fragment based strategy in the rational design of new potential AD medications.
痴呆症患者人数的增加和全球人口老龄化趋势促使我们需要开发新的药物来治疗复杂的生物学功能障碍，如与痴呆症相关的神经退行性变。阿尔茨海默病（AD）是最常见的痴呆症形式。在 AD 中，与认知有关的胆碱能信号传递会缓慢丧失，因此一线治疗方法是使用乙酰胆碱酯酶抑制剂来治疗症状，以增加乙酰胆碱水平。在五种获得 FDA 批准的 AD 药物中，多奈哌齐、加兰他敏和利伐斯的明是乙酰胆碱酯酶抑制剂，而美金刚，一种 N-甲基-D-天冬氨酸（NMDA）受体拮抗剂，可阻断高谷氨酸水平的作用。第五种药物由多奈哌齐和美金刚组成。尽管这些药物可以减轻和暂时减缓 AD 的症状，但它们不能阻止大脑损伤的进展。为了获得更好的治疗效果，需要多靶点药物。因此，科学家们越来越关注多靶点药物设计（MTDL）策略，试图开发同时调节多个生物靶点的混合分子。这篇综述重点介绍了基于配体的多靶点药物设计策略在合理设计新的潜在 AD 药物方面的最新实例。
