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作者中文名	作者英文名	单位中文名	单位英文名	E-Mail
宋紫腾	SONG Zi-teng	天津药物研究院天津市中药质量标志物重点实验室/中药现代制剂与质量控制技术国家地方联合工程实验室/药物成药性评价与系统转化全国重点实验室，天津 300462 和光中药科技（天津）有限公司，天津 300462	Tianjin Key Laboratory of Quality Marker of Traditional Chinese Medicine, National & Local United Engineering Laboratory of Modern Preparation and Quality Control Technology of Traditional Chinese Medicine, National Key Laboratory of Druggability Evaluation and Systematic Translational Medicine, Tianjin Institute of Pharmaceutical Research, Tianjin 300462, China Heguang Chinese Medicine Technology (Tianjin) Co., Ltd., Tianjin 300462, China
吴美琪	WU Mei-qi	沈阳药科大学中药资源教研室，辽宁沈阳 110016	Department of Traditional Chinese Medicinal Resources, Shenyang Pharmaceutical University, Shenyang 110016, China
韩彦琪	HAN Yan-qi	天津药物研究院天津市中药质量标志物重点实验室/中药现代制剂与质量控制技术国家地方联合工程实验室/药物成药性评价与系统转化全国重点实验室，天津 300462 和光中药科技（天津）有限公司，天津 300462	Tianjin Key Laboratory of Quality Marker of Traditional Chinese Medicine, National & Local United Engineering Laboratory of Modern Preparation and Quality Control Technology of Traditional Chinese Medicine, National Key Laboratory of Druggability Evaluation and Systematic Translational Medicine, Tianjin Institute of Pharmaceutical Research, Tianjin 300462, China Heguang Chinese Medicine Technology (Tianjin) Co., Ltd., Tianjin 300462, China
许浚*	XU Jun	天津药物研究院天津市中药质量标志物重点实验室/中药现代制剂与质量控制技术国家地方联合工程实验室/药物成药性评价与系统转化全国重点实验室，天津 300462 和光中药科技（天津）有限公司，天津 300462	Tianjin Key Laboratory of Quality Marker of Traditional Chinese Medicine, National & Local United Engineering Laboratory of Modern Preparation and Quality Control Technology of Traditional Chinese Medicine, National Key Laboratory of Druggability Evaluation and Systematic Translational Medicine, Tianjin Institute of Pharmaceutical Research, Tianjin 300462, China Heguang Chinese Medicine Technology (Tianjin) Co., Ltd., Tianjin 300462, China
张铁军*	ZHANG Tie-jun	天津药物研究院天津市中药质量标志物重点实验室/中药现代制剂与质量控制技术国家地方联合工程实验室/药物成药性评价与系统转化全国重点实验室，天津 300462 和光中药科技（天津）有限公司，天津 300462	Tianjin Key Laboratory of Quality Marker of Traditional Chinese Medicine, National & Local United Engineering Laboratory of Modern Preparation and Quality Control Technology of Traditional Chinese Medicine, National Key Laboratory of Druggability Evaluation and Systematic Translational Medicine, Tianjin Institute of Pharmaceutical Research, Tianjin 300462, China Heguang Chinese Medicine Technology (Tianjin) Co., Ltd., Tianjin 300462, China

基金项目:国家自然科学基金重点项目（81830111）

中文摘要:目的基于“性-效-物”理论研究原则，确定小儿消积止咳口服液（XEXJ）中的质量标志物（Q-marker）。方法通过分子对接实验确定化合物的药性（味），运用Schr?dinger 2020 Maestro软件进行酸、甘、苦、辛药味受体与相应化合物的分子对接。通过网络药理学和体外受体实验确定化合物的药效，利用数据库获取并整合得到化合物和疾病共有靶点，将其输入STRING网络分析平台筛选出核心靶点并进行生物信息学分析，运用Cytoscape软件构建网络图；通过G蛋白偶联受体和酶活法检测代表性成分对胆碱能受体毒蕈碱3（CHRM3）、肾上腺素受体β2（ADRB2）、ADRA1A、环氧合酶-2（COX-2）受体的作用。结果分子对接结果表明，有机酸类和香豆素类可能是XEXJ的酸味物质基础；糖类和简单苯丙素类可能是其甘味物质基础；木脂素、苯乙醇苷、黄酮、三萜类等成分可能是其苦味物质基础；生物碱类及部分黄酮类可能是其辛味物质基础。网络药理学分析发现，XEXJ可能通过作用于神经活性配体-受体相互作用、5-羟色胺能突触、环鸟苷酸-蛋白激酶G（cGMP-PKG）信号通路、钙信号通路等90条通路发挥促消化、止咳和解热抗炎功效。功能受体实验结果表明，XEXJ清热肃肺、消积止咳的作用机制可能与激活CHRM3、ADRB2受体，抑制ADRA1A、COX-2受体有关。综上，初步确定其Q-marker为橙皮苷、柚皮苷、新橙皮苷、去甲基川陈皮素、槲皮素-3-O-β-D-葡萄糖基-7-O-β-D-龙胆双糖苷、槲皮苷、异槲皮苷、金丝桃苷、山柰酚、连翘酯苷A、连翘酯苷E、连翘脂素、(+)-松脂素-β-D-吡喃葡萄糖苷、桔梗皂苷D、3,29-二苯甲酰栝楼仁三醇、辛弗林、槟榔碱、枸橼酸、绿原酸。结论基于“性-效-物”理论，采用分子对接、网络药理学和受体实验初步确定了XEXJ发挥药效作用的Q-marker，为其质量控制和作用机制研究提供参考依据。

中文关键词:小儿消积止咳口服液药性药效质量标志物

Study on Quality Markers of Xiao’er Xiaoji Zhike Oral Liquid Based on “Property-Response-Component”

Abstract:Objective To determine the quality markers (Q-marker) in Xiao'er Xiaoji Zhike Oral Liquid (XEXJ) based on the theory of "property-response-component".Methods The molecular docking experiment was used to determine the drug properties (tastes) of the compounds. Schr?dinger 2020 Maestro software was used to conduct molecular docking experiments between sour, sweet, bitter and pungent taste receptors and corresponding compounds. Network pharmacology and in vitro receptor experiments were used to determine the efficacy of compounds. Related databases were used to obtain and integrate the common targets of compounds and diseases, which were input into the STRING network analysis platform to screen out the core targets, and then bioinformatics analysis was performed. Cytoscape was used to construct the network. The effects of the representative components on cholinergic receptor muscarinic 3 (CHRM3), adrenergic receptor beta 2 (ADRB2), adrenergic receptor alpha 1A (ADRA1A) and cyclooxygenase-2 (COX-2) receptors were further detected by G protein-coupled receptor and enzyme activity assay.Results The results of molecular docking showed that the organic acids and coumarins may be the material basis for the sour taste of XEXJ. The saccharides and the simple phenylpropanoids may be the sweet material basis. The lignans, phenylethanoid glycosides, flavonoids and triterpenoids might be the material basis for the bitter taste. The alkaloids and flavonoids may be the material basis for the pungent taste. The results of network pharmacology showed that XEXJ may exert its pro-digestive, anti-tussive, anti-pyretic and anti-inflammatory effects via 90 pathways, such as neurotransmitter-receptor interactions, serotonergic synapse, cyclic guanosine monophosphate-protein kinase G (cGMP-PKG) signaling pathway, and calcium signaling pathway. The results of functional receptor experiments showed that the mechanism of XEXJ in clearing heat, resolving lung congestion, resolving accumulation and relieving cough may be related to the activation of CHRM3 and ADRB2 receptors and the inhibition of ADRA1A and COX-2 receptors. In conclusion, hesperidin, naringin, neohesperidin, demethylnobiletin, synephrine, arecoline, quercetin-3-O-β-D-glucose-7-O-β- D-gentiobioside, quercitrin, isoquercitrin, hyperoside, kaempferol, forsythoside A, forsythoside E, phillygenin, (+)-piresil-4-O-β-D-glucopyraside, platycodin D, 3,29-dibenzoyl rarounitriol, citric acid and chlorogenic acid might be the quality markers of XEXJ.Conclusion Based on the theory of "property-response-component", the quality markers of pharmacodynamic action of XEXJ were preliminarily determined by molecular docking, network pharmacology and receptor experiments, providing a reference for the quality control and mechanism research of XEXJ.

keywords:Xiao'er Xiaoji Zhike Oral Liquid property efficacy quality marker

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