文献类型：期刊文献

中文题名：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

英文题名：Explore the Molecular Mechanism of Treating Osteoarthritis with Huoluo Pill Based on Computer Aided Drug Design and Network Pharmacology

作者：张敏[1,5];邱璐[2];林佳[1,5];后叶虎[2];张慧娟[1,5];苟丽红[1,5];陶金正[3];姚娟[1,5];刘永琦[2,4];靳晓杰[1,2]

第一作者：张敏

机构：[1]甘肃中医药大学药学院,兰州730000;[2]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;[3]甘肃中医药大学临床医学院,兰州730000;[4]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;[5]西北中藏药协同创新中心,兰州730000

第一机构：甘肃中医药大学药学院（西北中藏药协同创新中心办公室）

年份：2022

卷号：39

期号：4

起止页码：450

中文期刊名：中国现代应用药学

外文期刊名：Chinese Journal of Modern Applied Pharmacy

收录：CSTPCD;;北大核心:【北大核心2020】；CSCD:【CSCD2021_2022】；

基金：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)

语种：中文

中文关键词：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

外文关键词：osteoarthritis;Huoluo pill;COX-2;5-LOX;F2;multi-target molecular docking;pharmacophore model;network pharmacology

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。
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 pharmacophore model 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.