杜仲中超氧化物歧化酶1抑制成分的虚拟筛选及分子动力学研究  

Virtual screening and molecular dynamics simulation studies of effective superoxide dismutase 1 inhibitory constituents from Eucommia ulmoides

作　　者：赵泽丰 亢恺雯 年梦 王强 乔海法 钱明成 ZHAO Zefeng;KANG Kaiwen;NIAN Meng;WANG Qiang;QIAO Haifa;QIAN Mingcheng(Shaanxi Key Laboratory of Acupuncture&Medicine,Xianyang 712046,China;College of Acupuncture&Massage,Shaanxi University of Chinese Medicine,Xianyang 712046,China;the Second College of Clinical Medicine,Shaanxi University of Chinese Medicine,Xianyang 712046,China;School of Pharmaceutical Engineering&Life Science,Changzhou University,Changzhou 213164,China)

机构地区：[1]陕西省针药结合重点实验室,咸阳712046 [2]陕西中医药大学针灸推拿学院,咸阳712046 [3]陕西中医药大学第二临床医学院,咸阳712046 [4]常州大学制药与生命科学学院,常州213164

出　　处：《西北药学杂志》2023年第1期124-132,共9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);陕西省科技厅中医诊疗装备研发相关研究创新团队项目(编号:303-202210705)。

摘　　要：目的对杜仲中潜在作用于超氧化物歧化酶1(superoxide dismutase 1,SOD1)靶点的抗肌萎缩性脊髓侧索硬化症(amyotrophic lateral sclerosis disease,ALS)活性物质进行研究,阐明其药效物质基础。方法收集文献中报道的具有抑制SOD1聚集活性的化合物信息,建立基于SOD1配体的HipHop药效团模型,收集文献中报道的杜仲中的成分并建立化合物库,对杜仲中的成分与药效团进行匹配,随后采用柔性对接手段对匹配到的小分子化合物与SOD1靶点(PDB ID:6A9O)进行对接并评估其相互作用。结果通过文献检索共得到杜仲中包含的化学成分118种,建立杜仲化合物库。通过测试集验证选出优选药效团02用于对杜仲化合物库的虚拟筛选,匹配后得到6种杜仲中潜在的抗ALS成分。通过分子模拟对接分析了6种化合物与SOD1的相互作用情况,预测所得的杜仲抗ALS成分与已有文献相符。采用分子动力学模拟手段对打分前2位的化合物进行了研究,结果表明,配体-受体复合物的稳定性与分子模拟对接结果基本保持一致。结论虚拟筛选结果表明基于药效团、分子对接及分子动力学模拟手段探讨杜仲中SOD1抑制成分具有一定的准确性。Objective To predict the anti-amyotrophic lateral sclerosis disease(ALS)active constituents on the target of superoxide dismutase 1(SOD1)from Eucommia ulmoides with the aid of pharmacophore and molecular docking.Methods SOD1 ligand-based pharmacophore model was set up and the molecular library of the constituents from E.ulmoides was established by collecting literature.Then the constituents from E.ulmoides were screened for the potential ALS 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 SOD1 protein(PDB ID:6 A9 O).The interactions were expressed including CDOCKER interaction energy,binding affinity,hydrogen bonds and non-bonding interactions.Results The molecular library of E.ulmoides contained 118 kinds of chemical constituents.According to the screening results by using pharmacophore model,6 kinds of potential constituents from E.ulmoides 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.The molecular dynamics simulation was carried out on the top 2 compounds to investigate the stability of the ligand-protein complex,which provided the similar results to the molecular docking.Conclusion The compounds screened from the pharmacophore model were consistent with the existing studies to different degrees,indicating that the virtual screen results of anti-ALS constituents from E.ulmoides based on pharmacophore,molecular docking and molecular dynamics simulation were reliable.

关 键 词：杜仲 肌萎缩性脊髓侧索硬化症 超氧化物歧化酶1 药效团 分子动力学模拟 

分 类 号：R914[医药卫生—药物化学]