气滞胃痛颗粒中延胡索抗炎镇痛作用的构效组学  

Structure-activity Omics of Anti-inflammatory and Analgesic Effect of Corydalis Rhizoma in Qizhi Weitong Granules

作　　者：秦鑫鹏 孟营 刘思聪 郑莹[1,2,3] 包永睿 王帅[1,2,3] 李天娇 韩凌[5] 邹薇 孟宪生[1,2,3] QIN Xinpeng;MENG Ying;LIU Sicong;ZHENG Ying;BAO Yongrui;WANG Shuai;LI Tianjiao;HAN Ling;ZOU Wei;MENG Xiansheng(College of Pharmacy,Liaoning University of Traditional Chinese Medicine(TCM),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;The Second People's Hospital of Dalian,Dalian 116011,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]大连市第二人民医院,辽宁大连116011 [5]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136-145,共10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延胡索含有化合物结构与抗炎镇痛的药效物质。方法:在课题组前期体外筛选的基础上,开展延胡索生物碱体内药效研究,以靶点为桥梁,将延胡索中一类或多类化学成分结构与药效紧密关联,将延胡索生物碱所含成分结构与抗炎镇痛疾病靶点进行分子对接,依据对接评分和延胡索生物碱结构母核的不同进行构效组学研究,总结其结合优劣的规律。结果:延胡索生物碱在体内抗炎镇痛药效研究中有良好效果,初步筛选延胡索生物碱中53个化学成分和73个靶点;抗炎镇痛疾病靶点3 074个,将成分靶点与抗炎镇痛疾病靶点取交集,共得到42个直接作用靶点;经过蛋白质-蛋白质相互作用(PPI)、分子对接等分析,最终得到延胡索生物碱的主要活性成分有延胡索乙素、巴马汀等,核心靶点为前列腺素内过氧化物合酶2(PTGS2)、代谢型谷氨酸受体5(GRM5)、雌激素受体1(ESR1)、钾依赖钠钙交换蛋白6(SLC6A4)、核蛋白转录因子(FOS)等;依据母核的不同将延胡索生物碱53个成分分为8类,其中原小檗碱类、小檗碱类、阿朴啡类三类成分多,并且与PTGS2、GRM5等靶点具有较好的结合,每组延胡索生物碱结构与对接评分关系呈现相同的规律。原小檗碱类结构中,母环的A环和D环上适当带有羟基、烷氧基或甲基的取代基有利于增强与两个靶点的结合活性。在小檗碱类结构中,含有13位甲基的结构对2个靶点结合更佳,推测甲基片段改变了成分结构与氨基酸残基的结合方式,极大地提高了其结合活性。结论:该研究采用构效组学研究方法,可以分析延胡索生物碱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 anti-inflammatory and analgesic effects of Corydalis Rhizoma by the means of structure-activity omics.Method:On the basis of the previous in vitro screening study,we studied the in vivo efficacy of the alkaloids in Corydalis Rhizoma.With the targets as a bridge,the structures of chemical components in Corydalis Rhizoma were connected with the efficacy.The molecular docking of the alkaloids in Corydalis Rhizoma with the targets of inflammation and pain was carried out.According to the docking scores and the differences in the structural nucleus of Corydalis Rhizoma alkaloids,a study of structure-activity omics was carried out to summarize the rules of their connection.Result:The alkaloids in Corydalis Rhizoma had good anti-inflammatory and analgesic effects in vivo,involving 53 chemical components and 73 targets.There were 3074 targets associated with inflammation and pain,and 42 targets of direct action were shared by the chemical components and the disease.The protein-protein interaction(PPI)and molecular docking analysis predicted that the main active components of Corydalis Rhizoma were tetrahydropalmatine and palmatine,and the core targets were prostaglandin endoperoxide synthase 2(PTGS2),glutamate receptor metabotropic 5(GRM5),estrogen receptor 1(ESR1),solute carrier family 6 member 4(SLC6A4),and fusion oncoproteins(FOS).According to the differences of mother nucleus,the 53 alkaloid components of Corydalis Rhizoma were classified into 8 categories,including protoberberine,berberine,and aporphine,which had high binding affinities with PTGS2,GRM5 and other targets.The relationship between the structures of Corydalis Rhizoma alkaloids and docking scores in each group showed the same law.In protoberberine,appropriate substituents with hydroxyl,alkoxy or methyl groups on the A and D rings of the parent ring were conducive to enhancing the binding activities with the two targets.In berberine,the structure containing a methyl group on position 13 had strong binding affinities with the two t

关 键 词：延胡索 生物碱 构效组学 分子对接 抗炎镇痛 

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