通过计算研究和生物学评估的结合发现选择性丁酰胆碱酯酶（BChE）抑制剂。

Discovery of Selective Butyrylcholinesterase (BChE) Inhibitors through a Combination of Computational Studies and Biological Evaluations.

机构信息

State Key Laboratory of Silkworm Genome Biology, College of Biotechnology, Southwest University, Chongqing 400715, China.

School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China.

出版信息

Molecules. 2019 Nov 20;24(23):4217. doi: 10.3390/molecules24234217.

As there are increased levels and activity of butyrylcholiesterase (BChE) in the late stage of Alzheimer's disease (AD), development of selective BChE inhibitors is of vital importance. In this study, a workflow combining computational technologies and biological assays were implemented to identify selective BChE inhibitors with new chemical scaffolds. In particular, a pharmacophore model served as a 3D search query to screen three compound collections containing 3.0 million compounds. Molecular docking and cluster analysis were performed to increase the efficiency and accuracy of virtual screening. Finally, 15 compounds were retained for biological investigation. Results revealed that compounds and could potently and highly selectively inhibit BChE activities (IC values < 10 μM on human BChE, selectivity index BChE > 30). These active compounds with novel scaffolds provided us with a good starting point to further design potent and selective BChE inhibitors, which may be beneficial for the treatment of AD.

由于在阿尔茨海默病（AD）晚期丁酸胆碱酯酶（BChE）的水平和活性增加，因此开发选择性 BChE 抑制剂至关重要。在这项研究中，我们实施了一种结合计算技术和生物测定的工作流程，以鉴定具有新型化学结构的选择性 BChE 抑制剂。具体来说，药效基团模型可用作 3D 搜索查询，以筛选包含 300 万种化合物的三个化合物库。进行了分子对接和聚类分析，以提高虚拟筛选的效率和准确性。最后，保留了 15 种化合物进行生物学研究。结果表明，化合物和能够强烈且高度选择性地抑制 BChE 活性（对人源 BChE 的 IC 值 < 10 μM，BChE 选择性指数 > 30）。这些具有新颖结构的活性化合物为我们进一步设计强效和选择性的 BChE 抑制剂提供了良好的起点，这可能有益于 AD 的治疗。