基于分子模拟技术何首乌中蒽醌类法尼基转移酶抑制剂的筛选  

Discovery of potential FTase inhibitors from anthraquinones of Polygoni Multiflori Radix based on molecular simulation

作　　者：李勇[1] 李登科[1] 李凯明[1] 孙震晓[1] LI Yong;LI Deng-ke;LI Kai-ming;SUN Zhen-xiao(Beijing University of Chinese Medicine,Beijing 100102,China)

机构地区：[1]北京中医药大学,北京100102

出　　处：《中国新药杂志》2018年第18期2164-2172,共9页Chinese Journal of New Drugs

基　　金：国家自然科学基金项目资助(81473418)

摘　　要：目的:以法尼基转移酶(farnesyltransferase,FTase)为载体,阐释何首乌蒽醌类化合物抗肿瘤作用的分子机制并筛选其中具有抑制FTase活性的化合物。方法:利用Common Feature Pharmacophore Generation(Hiphop)模块构建定性药效团,并根据评价参数获得最优药效团,利用最优药效团虚拟筛选何首乌蒽醌类化合物;利用分子对接技术精制筛选结果获得活性化合物并对活性化合物进行分析,以阐释何首乌蒽醌类化合物抗肿瘤作用的分子机制。结果:最优药效团模型包含3个疏水基团、2个氢键受体以及5个排除体积,其有效命中率(HRA)为92.47%、辨识有效性指数(IEI)为2.250、综合评价指数(CAI)为2.080。利用最优药效团筛选何首乌蒽醌类成分,初步获得3个潜在的蒽醌类活性成分;利用分子对接技术进一步筛选,得到大黄素-8-O-β-D-吡喃葡萄糖苷、大黄酚-8-O-β-D-吡喃葡萄糖苷、大黄素-8-O-(6'-O-乙酰基)-β-D-吡喃葡萄糖苷等3个化合物。结论:大黄素-8-O-β-D-吡喃葡萄糖苷、大黄酚-8-O-β-D-吡喃葡萄糖苷、大黄素-8-O-(6'-O-乙酰基)-β-D-吡喃葡萄糖苷能够抑制FTase的活性,是何首乌中蒽醌类化合物抗肿瘤的重要组分。Objective： To explore the antitumor mechanism of the anthraquinones of Polygoni Multiflori Radix using farnesyltransferase（ FTase） and discover potential FTase inhibitors. Methods： The qualitative pharmacophores were constructed by Common Feature Pharmacophore Generation（ Hiphop） method based on FTase. The optimal pharmacophore model was obtained by three indictors,including hit rate of active compounds（ HRA）,identification of effectiveness index（ IEI） and comprehensive evaluation index（ CAI）. The anthraquinones from the Polygoni Multiflori Radix were screened by the optimal pharmacophore model and the result was refined by molecular docking. Results： The optimal pharmacophore model contained three hydrophobics,two hydrogen bond acceptors and five excluded volumes and the values of HRA,IEI and CAI were 92. 47%,2. 250,and 2. 080,respectively. Ten potential active compounds were obtained by the optimal pharmacophore model and were refined by molecular docking. Finally three compounds were obtained, including emodin-8-O-β-D-glucopyranoside,chrysophanol-8-O-β-D-glucopyranoside,and emodin-8-O-（ 6＇-O-acetyl）-β-D-glucopyranoside. Conclusion： FTase can be inhibited by emodin-8-O-β-D-glucopyranoside,chrysophanol-8-O-β-D-glucopyranoside,and emodin-8-O-（ 6＇-O-acetyl）-β-D-glucopyranoside. The results suggest that the three compounds are important anti-tumor components of the anthraquinones from Polygoni Multiflori Radix.

关 键 词：何首乌 蒽醌类成分 FTase抑制剂 药效团 分子对接 

分 类 号：R96[医药卫生—药理学]