Using Topomer CoMFA and Surflex-dock to analyze 3D-QSAR of GSK-3β inhibitors and their mechanism of action

Authors :: Dandan Huang
Kan Zhong
Yonglan Liu
Guizhao Liang
Bozhi Shi
Guixue Wang
YaFei Zeng
YiQiang Shao
YueTing Li
Source :: SCIENTIA SINICA Chimica. 43:198-208
Publication Year :: 2013
Publisher :: Science China Press., Co. Ltd., 2013.
Abstract: GSK-3β的过度表达可导致人脑神经细胞内Tau蛋白的过磷酸化, 从而介导阿尔兹海默病(Alzheimer's disease, AD)的发生. 本文旨在研究GSK-3β的马来酰胺类抑制剂的三维定量构效关系(3D-QSAR)及新抑制剂分子与GSK-3β的作用机制. 采用基于R基团搜索技术的Topomer CoMFA建立了49个马来酰胺类GSK-3β抑制剂的3D-QSAR模型, 并用包括25个样本的测试集验证模型的外部预测能力. 所得优化模型的拟合、交互验证以及外部验证的复相关系数分别为0.928, 0.790和0.725. 采用Topomer search在ZINC分子数据库中进行虚拟搜索, 设计了28个可能具有更高活性的新抑制剂. 借助Surflex-dock分子对接研究了新抑制剂与GSK-3β作用模式与机制. 结果显示, 新抑制剂与GSK-3β的Asp133, Tyr134, Val135和Pro136等位点作用显著.

Subjects :: Quantitative structure–activity relationship
biology
Chemistry
General Chemical Engineering
Tau protein
General Chemistry
Biochemistry
Mechanism of action
Surflex dock
Materials Chemistry
medicine
biology.protein
medicine.symptom
GSK3B

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