| 引用本文: | 张敏,邱璐,林佳,后叶虎,张慧娟,苟丽红,陶金正,姚娟,刘永琦,靳晓杰.基于计算机辅助药物设计及网络药理学方法探究活络丸治疗骨关节炎的分子机制[J].中国现代应用药学,2022,39(4):450-460. |
| ZHANG Min,QIU Lu,LIN Jia,HOU Yehu,ZHANG Huijuan,GOU Lihong,TAO Jinzheng,YAO Juan,LIU Yongqi,JIN Xiaojie.Explore the Molecular Mechanism of Treating Osteoarthritis with Huoluo Pill Based on Computer Aided Drug Design and Network Pharmacology[J].Chin J Mod Appl Pharm(中国现代应用药学),2022,39(4):450-460. |
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| 基于计算机辅助药物设计及网络药理学方法探究活络丸治疗骨关节炎的分子机制 |
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张敏1,2, 邱璐3, 林佳1,2, 后叶虎3, 张慧娟1,2, 苟丽红1,2, 陶金正4, 姚娟1,2, 刘永琦3,5, 靳晓杰1,3
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1.甘肃中医药大学药学院, 兰州 730000;2.西北中藏药协同创新中心, 兰州 730000;3.甘肃中医药大学甘肃省高校重大疾病分子医学与中医药防治研究重点实验室, 兰州 730000;4.甘肃中医药大学临床医学院, 兰州 730000;5.甘肃中医药大学敦煌医学与转化教育部重点实验室, 兰州 730000
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| 摘要: |
| 目的 基于骨关节炎的发病机制以及临床药物需求,运用计算机辅助药物设计以及网络药理方法探究活络丸治疗骨关节炎的潜在药效成分及分子机制。方法 采用TCMSP、TCMID和化学专业数据库检索活络丸中药化合物。多靶点分子对接、结合自由能计算逐级对化合物与骨关节炎治疗靶点COX-2、5-LOX以及凝血因子F2的亲和力进行评估,对潜在活性化合物进行层次聚类及药效团模型的构建。利用Swiss Target Prediction预测化合物潜在靶点,Cytoscape构建"药味-成分-潜在靶点"网络。GeneCards、DrugBank、TTD和CTD检索骨关节炎疾病靶点。DAVID进行GO和KEGG分析,STRING分析蛋白相互作用。结果 分子对接及结合自由能计算获得了具有靶向COX-2、5-LOX、F2潜在亲和力的成分,经层次聚类分析后构建药效团模型,得到针对COX-2、5-LOX及F2的药效团模型AAH、AAA、AAR。裂叶苣荚莱内酯、芦荟大黄素、光甘草定等化合物具有的骨架结构可能对治疗骨关节炎有潜在作用。活络丸与骨关节炎共有靶点180个,PPI分析得到STAT3、SRC、CXCR4、EP300等潜在靶点179个,GO和KEGG分析得到GO条目686个、KEGG通路108条。结论 本研究选择花生四烯酸代谢靶点COX-2、5-LOX以及凝血靶点F2,通过多靶点分子对接和结合自由能计算逐级筛选、聚类分析、药效团模型及网络药理学等方法,初步揭示活络丸"多点显效,协同增效"的分子机制,为具有潜在较低不良反应的骨关节炎活性中药组分或组分配伍的开发提供靶点组合和研究基础。 |
| 关键词: 骨关节炎 活络丸 COX-2 5-LOX F2 多靶点分子对接 药效团模型 网络药理学 |
| DOI：10.13748/j.cnki.issn1007-7693.2022.04.004 |
| 分类号:R285.5 |
| 基金项目:国家自然科学基金项目(81960823)；国家自然科学基金青年科学基金项目(82004202)；甘肃省高等学校科研项目(2017A-048)；甘肃省教育厅高等学校产业支撑计划项目(2020C-15) |
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| Explore the Molecular Mechanism of Treating Osteoarthritis with Huoluo Pill Based on Computer Aided Drug Design and Network Pharmacology |
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ZHANG Min1,2, QIU Lu3, LIN Jia1,2, HOU Yehu3, ZHANG Huijuan1,2, GOU Lihong1,2, TAO Jinzheng4, YAO Juan1,2, LIU Yongqi3,5, JIN Xiaojie1,3
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1.Gansu University of Chinese Medicine, School of Pharmacy, Lanzhou 730000, China;2.Northwest Collaborative Innovation Center for Chinese Medicine, Lanzhou 730000, China;3.Gansu University of Chinese Medicine, Gansu University Key Laboratory for Molecular Medicine & Chinese Medicine Prevention and Treatment of Major Diseases, Lanzhou 730000, China;4.Gansu University of Chinese Medicine, School of Clinical Medicine, Lanzhou 730000, China;5.Gansu University of Chinese Medicine, Dunhuang Key Laboratory of Medicine and Transformation, Ministry of Education, Lanzhou 730000, China
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| Abstract: |
| OBJECTIVE To explore the potential pharmacodynamic components and molecular mechanism of Huoluo pill in the treatment of osteoarthritis by using computer aided drug design and network pharmacology based on the pathogenesis of osteoarthritis and the need for clinical drugs. METHODS TCMSP, TCMID and Chemistry database were used to search the traditional Chinese medicine compounds of Huoluo pill. The affinity of compounds for therapeutic targets of osteoarthritis such as COX-2, 5-LOX and coagulation factor F2 was evaluated by molecular docking and binding free energy calculations. The hierarchical clustering and pharmacophore model of potential active compounds were constructed. Swiss Target Prediction was used to predict the potential targets of compounds. Cytoscape constructed a network of "drug flavor-component-potential target". Genecards, DrugBank, TTD and CTD databases were used to search for osteoarthritis targets. DAVID performed GO and KEGG analyses, and STRING analyzed the target protein interactions.RESULTS The components with potential affinity for therapeutic targets of osteoarthritis such as COX-2, 5-LOX and coagulation factor F2 were obtained. The pharmacop was constructed after hierarchical cluster analysis, and the pharmacophore models AAH, AAA and AAR for COX-2, 5-LOX and F2 were obtained by molecular docking and binding free energy calculation. The skeleton structure represented by santamarine, aloe emodin and glabridin might had potential effect on the treatment of osteoarthritis. There were 180 targets in Huoluo pill and osteoarthritis. Through PPI analysis, 179 potential targets such as STAT3, SRC, CXCR4 and EP300 were obtained. Six hundred and eighty six GO items and one hundred and eight KEGG pathways were obtained through GO and KEGG analyses. CONCLUSION In this study, arachidonic acid metabolic targets COX-2, 5-LOX and coagulation target F2 are selected. Through multi-target molecular docking and binding free energy calculation step by step screening, cluster analysis, pharmacophore model and network pharmacology, the molecular mechanism of "multi-point effect and synergistic effect" of Huoluo pill is preliminarily revealed. It provides target combination and research basis for the development of active Chinese medicine components or component compatibility with osteoarthritis with low potential adverse reactions. |
| Key words: osteoarthritis Huoluo pill COX-2 5-LOX F2 multi-target molecular docking pharmacophore model network pharmacology |
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