In Vitro and In Silico Acetylcholinesterase Inhibitory Activity of Thalictricavine and Canadine and Their Predicted Penetration across the Blood-Brain Barrier
In Vitro and In Silico Acetylcholinesterase Inhibitory Activity of Thalictricavine and Canadine and Their Predicted Penetration across the Blood-Brain Barrier
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DOI：
10.3390/molecules24071340
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发表时间：
2019-04-05
期刊：
影响因子：
4.6
通讯作者：
Jun, Daniel
中科院分区：
文献类型：
--
作者：
Chlebek, Jakub;Korabecny, Jan;Jun, Daniel
近年来，从罂粟科植物Cordycava中分离出几种具有胆碱酯酶抑制作用的生物碱。用Ellman分光光度法测定了（+）-thalictricavine（1）和（+）-canadine（2）对人乙酰胆碱酯酶（hAChE）和丁酰胆碱酯酶（hBChE）的抑制活性。分子模拟用于检查化合物与hAChE活性位点口袋的结合模式。通过平行人工渗透试验（PAMPA）和logBB计算预测了1和2通过血脑屏障（BBB）的可能渗透性。在体外，发现1和2是选择性的hAChE抑制剂，IC 50值分别为0.38 +/- 0.05 μ M和0.70 +/- 0.07 μ M，但对hBChE被认为是无活性的（IC 50值> 100 μ M）。此外，这两种生物碱表现出竞争型模式的乙酰胆碱酯酶抑制和结合，最有可能的是，在相同的乙酰胆碱酯酶亚位点作为其底物。在硅片对接实验，使我们能够确认他们的结合姿态到活性中心的乙酰胆碱酯酶。根据PAMPA和logBB计算，2可能具有中枢活性，但1的BBB穿越有限。总之，1和2似乎是治疗阿尔茨海默病的潜在先导化合物。
In recent studies, several alkaloids acting as cholinesterase inhibitors were isolated from Corydalis cava (Papaveraceae). Inhibitory activities of (+)-thalictricavine (1) and (+)-canadine (2) on human acetylcholinesterase (hAChE) and butyrylcholinesterase (hBChE) were evaluated with the Ellman's spectrophotometric method. Molecular modeling was used to inspect the binding mode of compounds into the active site pocket of hAChE. The possible permeability of 1 and 2 through the blood-brain barrier (BBB) was predicted by the parallel artificial permeation assay (PAMPA) and logBB calculation. In vitro, 1 and 2 were found to be selective hAChE inhibitors with IC50 values of 0.38 +/- 0.05 mu M and 0.70 +/- 0.07 mu M, respectively, but against hBChE were considered inactive (IC50 values > 100 mu M). Furthermore, both alkaloids demonstrated a competitive-type pattern of hAChE inhibition and bind, most probably, in the same AChE sub-site as its substrate. In silico docking experiments allowed us to confirm their binding poses into the active center of hAChE. Based on the PAMPA and logBB calculation, 2 is potentially centrally active, but for 1 BBB crossing is limited. In conclusion, 1 and 2 appear as potential lead compounds for the treatment of Alzheimer's disease.