Multi-Target Screening and Experimental Validation of Natural Products from Selaginella Plants against Alzheimer's Disease.
Multi-Target Screening and Experimental Validation of Natural Products from Selaginella Plants against Alzheimer's Disease.
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卷柏植物天然产物抗阿尔茨海默病的多靶点筛选及实验验证
DOI：
10.3389/fphar.2017.00539
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发表时间：
2017
影响因子：
5.6
通讯作者：
Tan GS
中科院分区：
文献类型：
--
作者：
Deng YH;Wang NN;Zou ZX;Zhang L;Xu KP;Chen AF;Cao DS;Tan GS
阿尔茨海默病(AD)是一种进行性和不可逆转的神经退行性疾病，被认为是痴呆症最常见的原因。它不仅对学习记忆障碍有较大的影响，而且对社会经济也有较大的影响。目前，治疗阿尔茨海默病的药物主要是单一靶点药物，但由于阿尔茨海默病的复杂性和多种病因，很难获得理想的治疗效果。因此，多靶点药物的选择将是一种潜在的有效的治疗策略。为了从卷柏属植物中寻找治疗AD的多靶点活性成分，我们首先通过Morris水迷宫实验研究了卷柏总提取物对AD小鼠行为的影响，发现总提取物对AD小鼠的学习记忆功能有显著的改善作用。然后，基于随机森林(RF)和不同的描述子，建立AD相关蛋白的多目标SAR模型，初步筛选卷柏中潜在的活性成分。综合预测结果和实验室现有化合物的数量，选择13个化合物进行体外酶抑制实验，确定了4个具有BACE1/MAO-B双重抑制活性的化合物。最后，应用分子对接技术对预测结果进行了验证，并进行了酶抑制实验。在这些研究和验证过程的基础上，我们探索了一种基于微量天然产物和靶点数量来提高活性成分筛选效率的新策略，找到了一些具有生物活性的多靶点化合物，为开发治疗AD的新药奠定了基础。
Alzheimer's disease (AD) is a progressive and irreversible neurodegenerative disorder which is considered to be the most common cause of dementia. It has a greater impact not only on the learning and memory disturbances but also on social and economy. Currently, there are mainly single-target drugs for AD treatment but the complexity and multiple etiologies of AD make them difficult to obtain desirable therapeutic effects. Therefore, the choice of multi-target drugs will be a potential effective strategy inAD treatment. To find multi-target active ingredients for AD treatment from Selaginella plants, we firstly explored the behaviors effects on AD mice of total extracts (TE) from Selaginella doederleinii on by Morris water maze test and found that TE has a remarkable improvement on learning and memory function for AD mice. And then, multi-target SAR models associated with AD-related proteins were built based on Random Forest (RF) and different descriptors to preliminarily screen potential active ingredients from Selaginella. Considering the prediction outputs and the quantity of existing compounds in our laboratory, 13 compounds were chosen to carry out the in vitro enzyme inhibitory experiments and 4 compounds with BACE1/MAO-B dual inhibitory activity were determined. Finally, the molecular docking was applied to verify the prediction results and enzyme inhibitory experiments. Based on these study and validation processes, we explored a new strategy to improve the efficiency of active ingredients screening based on trace amount of natural product and numbers of targets and found some multi-target compounds with biological activity for the development of novel drugs for AD treatment.
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