Alzheimer's disease (AD) is a progressive neurodegenerative condition that leads to the gradual decline of neuronal cells. Despite significant interest and investment, complete prevention or treatment for AD and related dementia is still limited. The human acetylcholinesterase (hAChE) enzyme is a promising target for combating AD as it plays a crucial role in metabolising the neurotransmitter acetylcholine, which is essential for cognitive function and memory. The present study employed a multi-step approach, beginning with molecular docking to virtually screen 73 531 compounds from the PubChem library. Subsequently, we used Glide extra precision molecular docking to narrow down the list to three compounds (PubChem CID: 73058259, 141100002, and 44285707). The pharmacological and ADMET properties of the top three compounds were determined using multiple tools. The molecular dynamics (MD) simulation study at 500 ns revealed that all the ligands formed stable complexes with AChE. The trajectories of the ligands were stable, similar/better to the reference compound (donepezil), and identified compounds have drug-like features. This study presents the unique findings of structural and molecular features of new hAChE inhibitors and their dynamics, which have not been studied before. These insights could pave the way for developing more effective treatments for neurological conditions.

中文翻译：

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针对小分子的乙酰胆碱酯酶的结构和分子特征：利用计算机工具对抗阿尔茨海默病


阿尔茨海默病（AD）是一种进行性神经退行性疾病，会导致神经元细胞逐渐衰退。尽管人们对此产生了巨大的兴趣并投入了大量资金，但对 AD 和相关痴呆症的完全预防或治疗仍然有限。人类乙酰胆碱酯酶 (hAChE) 是对抗 AD 的一个有希望的靶点，因为它在神经递质乙酰胆碱的代谢中发挥着至关重要的作用，而神经递质乙酰胆碱对于认知功能和记忆至关重要。本研究采用多步骤方法，从分子对接开始，从 PubChem 库中虚拟筛选 73 531 种化合物。随后，我们使用 Glide 超精密分子对接将列表范围缩小到三种化合物（PubChem CID ： 73058259、141100002和44285707 ）。使用多种工具确定前三种化合物的药理学和 ADMET 特性。 500 ns 的分子动力学 (MD) 模拟研究表明，所有配体均与 AChE 形成稳定的复合物。配体的轨迹稳定，与参考化合物（多奈哌齐）相似/更好，并且鉴定的化合物具有药物样特征。这项研究提出了新型 hAChE 抑制剂的结构和分子特征及其动力学的独特发现，这是以前从未研究过的。这些见解可以为开发更有效的神经系统疾病治疗方法铺平道路。