对药远志-天麻中GABA-AT靶点抑制活性物质的虚拟筛选  

Virtual screening of effective GABA-AT inhibitory constituents from the pair herb Polygala tenuifolia and Gastrodia elata

作　　者：赵泽丰 郑晓晖[1] 年梦 乔海法 钱明成 ZHAO Zefeng;ZHENG Xiaohui;NIAN Meng;QIAO Haifa;QIAN Mingcheng(Northwest University,Xi'an 710069,China;Shaanxi University of Chinese Medicine,Xianyang 712046,China;School of Pharmacy,Changzhou University,Changzhou 213164,China)

机构地区：[1]西北大学,西安710069 [2]陕西中医药大学,咸阳712046 [3]常州大学药学院,常州213164

出　　处：《西北药学杂志》2023年第2期135-142,共8页Northwest Pharmaceutical Journal

基　　金：国家自然科学基金项目(编号:8210142829);陕西省自然科学基础研究项目(编号:2022JQ-823);陕西省教育厅科研计划项目(编号:21JS020);陕西中医药大学经脉-脏腑相关研究创新团队项目(编号:YL-09);陕西中医药大学博士科研启动金项目(编号:303-17102032024)。

摘　　要：目的 对对药远志-天麻中潜在作用于GABA转氨酶(GABA aminotransferase, GABA-AT)靶点的抗癫痫活性物质进行研究,阐明其药效物质基础。方法 收集文献中具有抑制GABA-AT活性的化合物信息,建立基于GABA-AT配体的HipHop药效团模型,收集文献中远志与天麻中的成分并建立化合物库,对远志与天麻中的成分与药效团进行匹配,采用柔性对接手段对匹配到的小分子化合物与GABA-AT靶点(PDB ID:1OHW)进行对接并评估其相互作用,采用体外酶活力法初步评价筛选到单体的GABA-AT的抑制活性。结果 通过文献检索共得到远志与天麻中化学成分26种,通过测试集验证选出优选药效团3用于对远志与天麻化合物库的虚拟筛选,匹配后得到10种远志与天麻中潜在的GABA-AT抑制成分。通过分子模拟对接分析了10种化合物对GABA-AT的作用情况,对其中4种单体进行了酶活力抑制能力评估。结论 基于药效团及分子模拟对接手段探讨远志与天麻中GABA-AT抑制成分具有一定的准确性。Objective This research is to predict anticonvulsant constituents targeting GABA aminotransferase(GABA-AT) from Traditional Chinese Medicine pair herbs Polygala tenuifolia and Gastrodia elata with the help of pharmacophore and molecular docking.Methods GABA-AT ligand-based pharmacophore model was set up and the molecular library of the constituents from P. tenuifolia and G. elata were established by collecting literature. Then the constituents from P. tenuifolia and G. elata were screened for the potential GABA-AT inhibitory potency in silico through matching with the best pharmacophore model. The Flexible Docking model was used to evaluate the interactions between promising hits screened from pharmacophore model and GABA-AT(PDB ID:1OHW). The interactions were expressed including CDOCKER interaction energy, binding affinity, hydrogen bonds and non-bonding interactions, initially evaluating the GABA-AT inhibitory activities of the monomers through in vitro enzymatic activity assay. In vitro GABA-AT enzymatic assay was performed to verify the GABA-AT inhibition preliminarily.Results The molecular library of P. tenuifolia and G. elata contains 26 kinds of chemical constituents. According to the screening results using pharmacophore model 3, 10 kinds of potential constituents were screened as the most potential hits among all the compounds. The molecular docking was conducted and the interaction patterns were given to show the detail interactions. Four kinds of screened monomers were selected to evaluated the in vitro GABA-AT inhibitory activity.Conclusion The compounds screened from the pharmacophore model were consistent with the existing studies to different degrees, indicating that the virtual screen results of anticonvulsant constituents from P. tenuifolia and G. elata based on pharmacophore and molecular docking are reliable.

关 键 词：远志 天麻 GABA-AT 抗癫痫 药效团 分子模拟对接 

分 类 号：R914[医药卫生—药物化学]