Center for Alzheimer Research, Karolinska Institutet; Department of Neurobiology, Care Sciences and Society; Division of Translational Alzheimer Neurobiology, NOVUM, 4th Floor, 141 86 Stockholm, Sweden.
Department of Chemistry, Uppsala University, Uppsala, Sweden.
Sci Rep. 2016 Aug 10;6:31247. doi: 10.1038/srep31247.
Recent reports have brought back the acetylcholine synthesizing enzyme, choline acetyltransferase in the mainstream research in dementia and the cholinergic anti-inflammatory pathway. Here we report, a specific strategy for the design of novel ChAT ligands based on molecular docking, Hologram Quantitative Structure Activity Relationship (HQSAR) and lead optimization. Molecular docking was performed on a series of ChAT inhibitors to decipher the molecular fingerprint of their interaction with the active site of ChAT. Then robust statistical fragment HQSAR models were developed. A library of novel ligands was generated based on the pharmacophoric and shape similarity scoring function, and evaluated in silico for their molecular interactions with ChAT. Ten of the top scoring invented compounds are reported here. We confirmed the activity of α-NETA, the only commercially available ChAT inhibitor, and one of the seed compounds in our model, using a new simple colorimetric ChAT assay (IC50 ~ 88 nM). In contrast, α-NETA exhibited an IC50 of ~30 μM for the ACh-degrading cholinesterases. In conclusion, the overall results may provide useful insight for discovering novel ChAT ligands and potential positron emission tomography tracers as in vivo functional biomarkers of the health of central cholinergic system in neurodegenerative disorders, such as Alzheimer's disease.
最近的报告将乙酰胆碱合成酶胆碱乙酰转移酶重新带回了痴呆症的主流研究中，以及胆碱能抗炎途径。在这里，我们报告了一种基于分子对接、全息定量构效关系（HQSAR）和先导优化的新型 ChAT 配体设计的特定策略。对一系列 ChAT 抑制剂进行了分子对接，以破译它们与 ChAT 活性位点相互作用的分子指纹。然后开发了强大的统计片段 HQSAR 模型。根据药效团和形状相似性评分函数生成了新型配体库，并在计算机上评估了它们与 ChAT 的分子相互作用。本文报道了排名前十的发明化合物。我们使用新的简单比色 ChAT 测定法（IC50≈88 nM）证实了唯一市售的 ChAT 抑制剂 α-NETA（也是我们模型中的一种起始化合物）的活性，而 α-NETA 对 ACh 降解的胆碱酯酶的 IC50 约为 30 μM。总之，总体结果可能为发现新型 ChAT 配体和潜在的正电子发射断层扫描示踪剂提供有用的见解，这些配体和示踪剂可用作神经退行性疾病（如阿尔茨海默病）中中枢胆碱能系统健康的体内功能生物标志物。
