气滞胃痛颗粒中枳壳抗炎镇痛作用的构效组学

Structure-activity Omics on Anti-inflammatory and Analgesic Effect of Aurantii Fructus in Qizhi Weitong Granules

目的:采用构效组学研究方法,阐释气滞胃痛颗粒中枳壳黄酮发挥抗炎镇痛作用的药效物质。方法:在课题组前期体外药效筛选的基础上,开展枳壳黄酮体内药效研究,运用中药系统药理数据库和分析平台(TCMPS),人类在线孟德尔遗传数据库(OMIM),检索互作基因(STRING)等网络数据库,获取枳壳黄酮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枳壳黄酮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;以靶点为桥梁,将枳壳中一类或多类化学成分结构与药效紧密关联,通过各类结构与药效靶点结合规律探讨药效明确的化合物与药效之间的构效关系。结果:枳壳黄酮对葡聚糖硫酸钠(DSS)结肠炎小鼠具有良好的抗炎镇痛药效,能够改善结肠炎小鼠体征,明显降低炎症因子白细胞介素-6(IL-6)、白细胞介素-1β(IL-1β)水平(P<0.05),获得枳壳黄酮类活性成分12个,按照母核进行结构归类,其中二氢黄酮类9个,黄酮类3个。经韦恩(Venn)交互分析,得到枳壳抗炎镇痛靶点167个,通过度值(Degree)和分子对接综合评分,选择前列腺素内过氧化物合酶2(PTGS2)和丝裂原活化蛋白激酶3(MAPK3)进行进一步的结构分析。通过结构分析发现,含有糖苷类结构的成分与抗炎镇痛靶点结合活性更高。结论:该研究在体内药效实验的基础上采用构效组学的研究方法,可以分析枳壳黄酮抗炎镇痛的物质基础,同时构效组学为中药药效物质的阐释提供新思路新方法。

Objective:To explain the pharmacodynamic substances of Aurantii Fructus flavonoids that exert anti-inflammatory and analgesic effects using a structure-activity omics approach.Method:On the basis of the previous in vitro pharmacological screening conducted by the research team,an in vivo pharmacological study of Aurantii Fructus flavonoids was carried out.Core targets of the anti-inflammatory and analgesic active components of flavonoids of Aurantii Fructus were identified using various network databases,including the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform(TCMSP),the Online Mendelian Inheritance in Man(OMIM),and the Search Tool for the Retrieval of Interacting Genes/Proteins(STRING).Computer-aided virtual screening technology was used to dock different types of Aurantii Fructus flavonoids with core targets.The key core targets with high binding activity were selected based on the comprehensive scores of each target and the active structures.Using these targets as bridges,the structures of one or more types of chemical components in Aurantii Fructus were closely linked to pharmacological effects.The structure-activity relationship between the clear pharmacodynamic compounds and their effects was explored through the binding patterns of various structures with pharmacodynamic targets.Result:Aurantii Fructus flavonoids demonstrated significant anti-inflammatory and analgesic effects on dextran sulfate sodium(DSS)-induced colitis in mice,which could improve symptoms and significantly reduce the levels of inflammatory factors interleukin-6(IL-6)and interleukin-1β(IL-1β)(P<0.05).Twelve active components of Aurantii Fructus flavonoids were identified and categorized into nine dihydroflavonoids and three flavonoids based on their structures of the parent nuclei.Through Venn analysis,167 anti-inflammatory and analgesic targets for Aurantii Fructus were identified.Based on degree value and molecular docking comprehensive scores,prostaglandin-endoperoxide synthase 2(PTGS2)and mitogen-activated protein kinase 3(MAPK3)were selected for further structural analysis.Structural analysis revealed that components containing glycoside structures exhibited higher binding activity with anti-inflammatory and analgesic targets.Conclusion:This study utilized a structure-activity omics approach based on in vivo pharmacodynamic experiments to analyze the material basis of the anti-inflammatory and analgesic effects of Aurantii Fructus flavonoids.The structure-activity omics approach provides new ideas and methods for elucidating the pharmacodynamic substances of Chinese medicine.