Graduate Institute of Biotechnology, National Taipei University of Technology, 1 Sec. 3 ZhongXiao E, Rd., Taipei, 10608, Taiwan.
J Biomed Sci. 2011 Jan 21;18(1):8. doi: 10.1186/1423-0127-18-8.
Alzheimer's disease (AD) is the most common cause of dementia characterized by progressive cognitive impairment in the elderly people. The most dramatic abnormalities are those of the cholinergic system. Acetylcholinesterase (AChE) plays a key role in the regulation of the cholinergic system, and hence, inhibition of AChE has emerged as one of the most promising strategies for the treatment of AD.
In this study, we suggest a workflow for the identification and prioritization of potential compounds targeted against AChE. In order to elucidate the essential structural features for AChE, three-dimensional pharmacophore models were constructed using Discovery Studio 2.5.5 (DS 2.5.5) program based on a set of known AChE inhibitors.
The best five-features pharmacophore model, which includes one hydrogen bond donor and four hydrophobic features, was generated from a training set of 62 compounds that yielded a correlation coefficient of R = 0.851 and a high prediction of fit values for a set of 26 test molecules with a correlation of R² = 0.830. Our pharmacophore model also has a high Güner-Henry score and enrichment factor. Virtual screening performed on the NCI database obtained new inhibitors which have the potential to inhibit AChE and to protect neurons from Aβ toxicity. The hit compounds were subsequently subjected to molecular docking and evaluated by consensus scoring function, which resulted in 9 compounds with high pharmacophore fit values and predicted biological activity scores. These compounds showed interactions with important residues at the active site.
The information gained from this study may assist in the discovery of potential AChE inhibitors that are highly selective for its dual binding sites.
阿尔茨海默病（AD）是老年人进行性认知功能障碍最常见的原因。最明显的异常是胆碱能系统。乙酰胆碱酯酶（AChE）在胆碱能系统的调节中起着关键作用，因此，抑制 AChE 已成为治疗 AD 的最有前途的策略之一。
在本研究中，我们提出了一种针对 AChE 的潜在化合物的鉴定和优先级排序的工作流程。为了阐明 AChE 的基本结构特征，使用 Discovery Studio 2.5.5（DS 2.5.5）程序基于一组已知的 AChE 抑制剂构建了三维药效团模型。
最佳的五特征药效团模型，包括一个氢键供体和四个疏水性特征，是从一组 62 种化合物的训练集中生成的，该模型的相关系数 R = 0.851，对一组 26 种测试分子的拟合值预测也很高，相关系数 R² = 0.830。我们的药效团模型还具有较高的 Güner-Henry 分数和富集因子。对 NCI 数据库进行虚拟筛选获得了新的抑制剂，这些抑制剂有可能抑制 AChE 并保护神经元免受 Aβ毒性的影响。随后对命中化合物进行分子对接，并通过共识评分函数进行评估，结果得到了 9 种具有高药效团拟合值和预测生物活性评分的化合物。这些化合物与活性位点的重要残基相互作用。
本研究获得的信息可能有助于发现对其双重结合位点具有高选择性的潜在 AChE 抑制剂。
