气滞胃痛颗粒中柴胡抗炎镇痛作用的构效组学  

Structure-activity Omics on Anti-inflammatory and Analgesic Effect of Bupleuri Radix in Qizhi Weitong Granules

作　　者：罗曦 齐冰[1,2,3] 孟营 秦鑫鹏 包永睿 李天娇[1,2,3] 王亮 王帅[1,2,3] 孟宪生 LUO Xi;QI Bing;MENG Ying;QIN Xinpeng;BAO Yongrui;LI Tianjiao;WANG Liang;WANG Shuai;MENG Xiansheng(College of Pharmacy,Liaoning University of Traditional Chinese Medicine,Dalian 116600,China;Liaoning Multi-dimensional Analysis of TCM Technical Innovation Center,Dalian 116600,China;Liaoning Province Modern TCM Research and Engineering Laboratory,Dalian 116600,China;China Resources Sanjiu Medical&Pharmaceutical Co.Ltd.,Shenzhen 518110,China)

机构地区：[1]辽宁中医药大学药学院,辽宁大连116600 [2]辽宁省中药多维分析专业技术创新中心,辽宁大连116600 [3]辽宁省现代中药研究工程实验室,辽宁大连116600 [4]华润三九医药股份有限公司,广东深圳518110

出　　处：《中国实验方剂学杂志》2024年第15期146-153,共8页Chinese Journal of Experimental Traditional Medical Formulae

基　　金：中央引导地方科技发展专项(2021JH6/10500012);辽宁省科技创新领军人才项目(XLYC1902116)。

摘　　要：目的:采用构效组学研究方法,阐释气滞胃痛颗粒中柴胡抗炎镇痛作用的药效物质。方法:采用甲醛小鼠致痛实验明确柴胡皂苷的体内抗炎镇痛作用;运用中药系统药理数据库和分析平台(TCMSP),人类在线孟德尔遗传数据库(OMIM)和检索互作基因(STRING)等网络数据库,获取并筛选柴胡抗炎镇痛活性成分的核心靶点;采用计算机虚拟筛选技术将不同类型的柴胡皂苷与核心靶点进行对接,以各靶点与活性结构的综合评分总分为遴选原则,得到高结合活性的关键核心靶点;通过各类结构与药效靶点结合规律探讨分析构效关系。结果:柴胡皂苷能够降低甲醛刺激引起的小鼠足部肿胀,并在甲醛引发小鼠足部炎性疼痛反应中能使前列腺素E2(PGE2)含量下降,对PGE2所引发的炎性疼痛有显著的抑制作用;筛选出柴胡皂苷中9个化学成分和39个靶点;抗炎镇痛靶点3074个,将成分靶点与抗炎镇痛疾病靶点取交集,共得到22个直接作用靶点;经过蛋白质-蛋白质相互作用(PPI)分析,最终得到药物的主要活性成分有柴胡皂苷a、柴胡皂苷b1、柴胡皂苷b2、柴胡皂苷b3、柴胡皂苷c、柴胡皂苷d、柴胡皂苷e、柴胡皂苷f、柴胡皂苷v;关键靶点为fms相关受体酪氨酸激酶1(FLT1)、可溶性血管内皮生长因子受体(KDR)、成纤维细胞生长因子2(FGF2)、血管内皮生长因子A(VEGFA)、信号传导及转录激活因子3(STAT3)等;将柴胡中活性成分与PPI网络中度值前5的靶点进行分子对接,共得到>5分的高活性对接25个,其中5~6分的6个,>6分的18个。结论:该研究基于柴胡皂苷的体内抗炎镇痛药效作用,采用构效组学研究方法,可以分析柴胡皂苷抗炎镇痛的药效物质。构效组学能够为中药药效物质的阐释提供新思路、新方法。Objective:To identify the pharmacodynamic substances for the anti-inflammatory and analgesic effects of Bupleuri Radix by structure-activity omics.Method:A mouse model of pain was established with formaldehyde to examine the anti-inflammatory and analgesic effects of saikosaponins in vivo.The core targets of the active components in Bupleurum Radix for the anti-inflammatory and analgesic effects were screened from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform(TCMSP),Online Mendelian Inheritance in Man(OMIM),and Search Tool for Recurring Instances of Neighbouring Genes(STRING).The key core targets with high binding affinity were screened based on the comprehensive score in the molecular docking between different types of saikosaponins and core targets.The structure-activity relationship was discussed and analyzed based on the binding of compounds to pharmacodynamic targets.Result:Saikosaponins alleviated the foot swelling induced by formaldehyde and reduced the content of prostaglandin E2(PGE2)in the mouse model,showcasing a significant inhibitory effect on the inflammatory pain caused by PGE2.Nine components and 39 targets of saikosaponins,as well as 3074 targets of anti-inflammatory and analgesic effects were screened out,and 22 common targets shared by saikosaponins and the effects were obtained as the direct targets.The protein-protein interaction(PPI)analysis showed that the main active components of Bupleurum Radix were saikosaponins a,b1,b2,b3,c,d,e,f,and v,and the key targets were fms-related receptor tyrosine kinase 1(FLT1),kinase insert domain receptor(KDR),fibroblast growth factor 2(FGF2),vascular endothelial growth factor A(VEGFA),and signal transducer and activator of transcription 3(STAT3).Molecular docking between saikosaponins and the top 5 targets with high degrees in PPI network analysis revealed 25 highly active docks,including 6 docks with scores of 5-6 and 18 docks with scores above 6.Conclusion:This study adopted structural-activity omics to analyze the

关 键 词：抗炎镇痛 柴胡皂苷 构效组学 分子对接 蛋白质-蛋白质相互作用(PPI) 

分 类 号：R284.2[医药卫生—中药学] R285[医药卫生—中医学] R289R287R22R2-031R33R24