基于网络药理学和分子对接技...药对治疗癌性发热的作用机制_谢虹亭.pdf

论著生物信息技术基金项目:国家自然科学基金(81973640)作者简介:谢虹亭(1998 )，女，在读硕士研究生，研究方向:中西医结合肿瘤学。通信作者:朱世杰(1972 )，男，博士，主任医师，研究方向:中西医结合肿瘤学。基于网络药理学和分子对接技术探讨柴胡-黄芩药对治疗癌性发热的作用机制谢虹亭1，2谢飞宇1，2龙思丹1，2陈美池1，2薛鹏2朱世杰2(1 北京中医药大学研究生院，北京市100029;2 中国中医科学院望京医院肿瘤科，北京市100102)【摘要】目的基于网络药理学和分子对接技术探讨柴胡-黄芩药对治疗癌性发热的作用机制。方法利用中药系统药理学数据库与分析平台搜索柴胡、黄芩的活性化学成分及其作用靶点，并应用 GeneCards 数据库、OMIM 数据库、TTD 数据库获得癌性发热相关靶点。对柴胡、黄芩活性化学成分相关靶点与癌性发热相关靶点进行取交集;针对交集靶点，利用 STING 110 数据库及 CytoScape 3 7 2 软件建立蛋白质-蛋白质相互作用网络及推测网络中的潜在蛋白质功能模块，并基于 Metascape 平台进行基因本体论(GO)功能富集分析与京都基因与基因组百科全书(KEGG)通路富集分析。利用 CytoScape 372 软件建立药物成分-交集靶点-通路网络图，并根据拓扑参数推断柴胡-黄芩药对治疗癌性发热的核心活性化学成分、核心靶点、核心通路;利用 AutoDock1 5 6 软件对上述核心活性化学成分和核心靶点进行分子对接。结果(1)共得到柴胡-黄芩药对的 42 个活性化学成分和178 个作用靶点，癌性发热相关靶点1562 个，交集靶点98 个，2 个潜在蛋白质功能模块。(2)GO 功能富集分析提示交集靶点主要涉及对脂多糖、细菌和脂质的应答，以及对凋亡信号通路、血管形态形成等的调控。KEGG 通路富集分析提示交集靶点主要涉及癌症相关通路、肿瘤坏死因子(TNF)信号通路、白细胞介素(IL)-17 信号通路、丝裂原活化蛋白激酶(MAPK)通路和肝炎通路等。(3)柴胡的檞皮素、山奈酚和异鼠李素，以及黄芩的汉黄芩素和黄芩素为柴胡-黄芩治疗癌性发热的核心活性化学成分;前列腺素内过氧化物合成酶(PTGS)2、PTGS1、丝氨酸蛋白酶1(PSS1)、Caspase-3、蛋白激酶 B(AKT1)为治疗癌性发热的核心靶点;柴胡-黄芩药对主要通过癌症相关通路治疗癌性发热，同时也涉及肝炎通路、MAPK 通路、TNF 通路和 IL-17 通路。(4)分子对接技术结果显示，PSS1、AKT1 与檞皮素，AKT1 与山奈酚，PTGS1 与黄芩素，Caspase-3、PTGS1 与异鼠李素的对接结合能均 5，提示筛选出的核心活性化学成分与核心靶点具有较好的结合活性。结论柴胡-黄芩药对中的檞皮素、山奈酚、异鼠李素、黄芩素和汉黄芩素能够抑制 PTGS2、PTGS1、PSS1、AKT1、Caspase-3 基因的表达从而减少前列腺素合成、抑制肿瘤增殖，并通过抑制癌症相关通路、MAPK 通路、TNF 通路、IL-17 通路的激活，从而减少 IL-1、IL-6、TNF-等致热细胞因子的释放。柴胡-黄芩药对同时发挥抗肿瘤和抗炎解热两方面作用，从而达到治疗癌性发热的目的。【关键词】癌性发热;柴胡;黄芩;和解少阳法;网络药理学;分子对接技术;作用机制【中图分类号】730 6;273【文献标识码】A【文章编号】0253-4304(2022)23-2771-09DOI:10 11675/j issn 0253-4304 2022 23 13Exploration of adix Bupleuri-adix Scutellariae herb pair for the treatment of cancerousfever:a mechanism study based on network pharmacology and molecular docking techniqueXIE Hong-ting1，2，XIE Fei-yu1，2，LONG Si-dan1，2，CHEN Mei-chi1，2，XUE Peng2，ZHU Shi-jie2(1 Graduate School，Beijing University of Chinese Medicine，Beijing 100029，China;2 Department of Oncology，Wang Jing Hospital of China Academy of Chinese Medical Sciences，Beijing 100102，China)【Abstract】ObjectiveTo explore the mechanism of adix Bupleuri-adix Scutellariae herb pair for the treatmentof cancerous fever based on network pharmacology and molecular docking technique MethodsThe active chemicalcomponents of adix Bupleuri and adix Scutellariae and their effect targets were searched from the TraditionalChinese Medicine Systems Pharmacology Database and Analysis Platform，and the targets related to cancerous fever wereobtained from the databases of GeneCards，OMIM and TTD The intersection on targets related to active chemical1772广西医学2022 年 12 月第 44 卷第 23 期components of adix Bupleuri and adix Scutellariae with targets related to cancerous fever was obtained;in addition，for intersection targets，the protein-protein interaction network was constructed and the potential protein functionalmodules in the network were speculated by the STING 11 0 database and CytoScape 3 7 2 software The GeneOncology(GO)functional enrichment analysis and Kyoto Encyclopedia of Genes and Genomes(KEGG)pathwayenrichment analysis were performed based on Metascape platform The CytoScape 3 7 2 software was used toconstruct drug components-intersection targets-pathway network，and the core active chemical components，coretargets and core pathways of adix Bupleuri-adix Scutellariae herb pair for the treatment of cancerous fever werespeculated according to topological parameters The molecular docking was performed on aforesaid core active chemicalcomponents and core targets by AutoDock 1 5 6 software esults(1)A total of 42 active chemical componentsand 178 effect targets of adix Bupleuri-adix Scutellariae herb pair were obtained，and there were 1562 targets relatedto cancerous fever and 98 intersection targets，as well as 2 potential protein functional modules(2)The GO functionalenrichment analysis indicated that intersection targets mainly concerned the responses to lipopolysaccharide，bacteriaand lipid，as well as regulation on apoptotic signaling pathway and blood vessel morphogenesis，etc The KEGGpathway enrichment analysis implied that intersection targets were mainly consisted of pathways in cancer，tumor necrosisfactor(TNF)signaling pathway，interleukin(IL)-17 signaling pathway，mitogen-activated protein kinase(MAPK)pathway and hepatitis pathway(3)Quercetin，kaempferol and isorhamnetin of adix Bupleuri，and wogonin andbaicalein of adix Scutellariae were core active chemical components of adix Bupleuri-adix Scutellariae for treatingcancerous fever;furthermore，prostaglandin endoperoxide synthase(PTGS)2，PTGS1，serine protease 1(PSS1)，Caspase-3，protein kinase B(AKT1)were core targets for treating cancerous fever，and herb pair of adix Bupleuri-adixScutellariae treated cancerous fever mainly through pathways in cancer，simultaneously concerning hepatitis pathway，MAPKpathway，TNF pathway and IL-17 pathway(4)The results of molecular docking technique revealed that docking bindingenergies of PSS1，AKT1 with quercetin，AKT1 with kaempferol，PTGS1 with baicalein，and Caspase-3，PTGS1 withisorhamnetin were all 5，indicating a relatively good binding activ