目的 整理分析含有石膏的古方，挖掘石膏在治疗热证时的配伍用药规律，并结合“有机小分子活性成分与无机金属离子”间的配位化学探究其解热的物质基础。方法 收集《中医方剂大辞典》中含有石膏且具有解热作用的方剂，构建方药数据库，利用Microsoft Excel 2019统计各中药出现频次，通过SPSS Modeler 18.0对方剂中的药物进行关联规则分析，得到核心药物组合。运用网络药理学分析核心药物组合，得到核心靶点，并进行蛋白互作分析以及基因本体（gene ontology，GO）和京都基因与基因组百科全书（Kyoto encyclopedia of genes and genomes，KEGG）富集分析；用等温滴定量热仪滴定核心药物组合，验证其是否发生反应；梳理中药有机活性成分-金属配合物研究进展，探究石膏解热物质基础。结果 共纳入方剂1440首，以汤剂、散剂为主；涉及中药770味，其中与石膏配伍的高频中药29味（频次≥100），以清热药、补虚药、解表药为主。关联规则分析得到二项关联16条，其中核心药物组合“石膏-黄芩”和“石膏-甘草”的有效成分分别为43、99个，与发热的交集靶点有51、94个。GO和KEGG富集分析结果显示，2个核心药物组合很可能以调控核转录因子-κB（nuclear factor-κB，NF-κB）信号通路为主，同时调控白细胞介素（inter leukin-6，IL-6）、肿瘤坏死因子（tumor necrosis factor，TNF）、一氧化氮（nitric oxide，NO）等细胞因子及丝裂原活化蛋白激酶（mitogen activated protein kinases，MAPK）信号通路、TNF信号通路等，协同发挥作用。以核心药物组合“石膏-黄芩”为例，等温滴定量热实验结果显示黄芩和石膏互作强烈，而其主要有效成分黄芩苷和钙离子也发生了配位反应，证明黄芩中的活性成分和石膏中的金属离子可发生相互作用。通过梳理中药有机活性成分-金属配合物研究进展，推测石膏药效的发挥与其中金属元素和配伍中药有机活性成分形成配合物密切相关。结论 利用“干法＋湿法实验”结合“配位化学”理念，探究石膏解热配伍规律及物质基础，石膏在自身发挥解热作用的同时，其中丰富的元素可与配伍中药中的黄酮类、蒽醌类、多糖类等有机活性成分形成配合物，从而增强生物活性，发挥协同作用，以期为石膏解热物质基础及机制的探究提供新的方向。

Objective To sort out and analyze the ancient prescriptions containing Shigao (Gypsum Fibrosum), to explore the rule of compatibility of Gypsum Fibrosum in the treatment of fever, and its antipyretic material basis combined with coordination chemistry between the active components of organic small molecules and inorganic metal ions. Methods The prescriptions containing Gypsum Fibrosum and antipyretic effect in the Dictionary of Traditional Chinese Medicine Prescriptions were collected, and the prescription database was constructed. The occurrence frequency of each traditional Chinese medicine (TCM) was counted by Microsoft Excel 2019, and the core drug combinations were obtained by analyzing the association rules of the drugs in the prescription by SPSS Modeler 18.0. The core drug combinations were analyzed by network pharmacology, and the core targets were obtained. Protein interaction analysis and gene ontology (GO) and Kyoto encyclopedia of genes and genomes (KEGG) enrichment analysis were carried out. The core drug combination was titrated by isothermal titration calorimeter to verify whether it reacted or not. The research progress of organic components of TCM-metal complex was summarized, and the material basis of antipyretic substance of Gypsum Fibrosum was explored. Results Through screening 1440 prescriptions were included, mainly decoctions and powders. A total of 770 TCMs were involved, including 29 high-frequency drugs compatible with Gypsum Fibrosum (frequency ≥ 100), which were mainly heat-clearing TCMs, deficiency-tonifying TCMs and exterior-releasing TCMs. Sixteen two-item associations were obtained by association rule analysis, in which the active components of the core drug combinations "Gypsum Fibrosum-Huangqin (Scutellariae Radix)" and "Gypsum Fibrosum-Gancao (Glycyrrhizae Radix et Rhizoma)" were 43 and 99 respectively, and 51 and 94 targets were intersected with fever. The results of GO and KEGG enrichment analysis showed that the combinations of the two core drugs probably regulated nuclear factor-κB (NF-κB) signal pathway mainly, cytokines such as inter leukin-6 (IL-6), tumor necrosis factor (TNF), nitric oxide (NO), mitogen activated protein kinases (MAPK) signal pathway, TNF signal pathway were played a synergistic role. Taking the core drug combination "Gypsum Fibrosum-Scutellariae Radix" as an example, the results of isothermal titration calorimetry test showed that there was a strong interaction between Scutellariae Radix and Gypsum Fibrosum, and the coordination reaction between baicalin and calcium ion also occurred. It was proved that the active components of Scutellariae Radix can interact with the metal ions in Gypsum Fibrosum. Through combing the research progress of organic active components of TCM-metal complexes, it was inferred that the efficacy of Gypsum Fibrosum was closely related to the formation of complexes between metal elements and organic components of TCM. Conclusion The "dry-method + wet-method" combined with the concept of "coordination chemistry" were used to explore the antipyretic compatibility law and material basis of Gypsum Fibrosum. It was considered that while Gypsum Fibrosum played an antipyretic role, rich elements could be partitioned with flavonoids, anthraquinones and polysaccharides in TCM to form complexes, so as to enhance biological activity and play a synergistic effect, with view to providing a new direction for the study of antipyretic material basis of Gypsum Fibrosum.

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北京市自然科学基金面上项目（7202116）；国家自然科学基金项目（82073974）；北京市科技新星计划（Z201100006820026）；中华中医药学会青年人才托举工程项目（CACM-2018-QNRC2-B08）；北京中医药大学重点攻关项目（2020-JYB-ZDGG-044）；中央高校基金科研业务项目（杰出青年基金BUCM-2019-JCRC002，岐黄团队2019-JYB-TD005）；北京市中药基础与新药研究重点实验室