目的 利用分子对接和网络药理学的方法预测桂枝芍药知母汤治疗类风湿关节炎的主要活性成分和作用靶点，结合中医方解配伍理论对其多成分-多靶点-多通路的作用进行分析。方法 在TCMSP、TCM-Datebase@Taiwan、PubChen Compound数据库收集桂枝芍药知母汤中9味中药（桂枝、芍药、知母、甘草、麻黄、生姜、白术、防风、附子）的主要化学成分。通过DrugBank、TTD数据库查找与类风湿关节炎治疗相关的蛋白靶点，并上传到String在线数据库，构建蛋白互作网络关系。在PDB数据库下载合适的蛋白靶点晶体结构，采用Discovery studio 4.5.0软件进行化合物与靶点的分子对接，利用Cytoscape 3.6.1软件，构建药物-化合物-靶点可视化网络，阐释桂枝芍药知母汤抗类风湿关节炎的主要作用机制。结果 分子对接结果显示桂枝芍药知母汤中存在316个潜在的抗关节炎活性成分，作用于26个靶点，其中MAPK1、ZADH2、P38、AKR1C2、DHODH、CA2、MMP3、MMP9、RANKL等蛋白是主要作用靶点。生物功能和通路分析提示，桂枝芍药知母汤的作用机制主要涉及骨吸收（28%）、组蛋白激酶活性（20%）、肽基酪氨酸磷酸化（20%）、前列腺素代谢过程（12%）等生物过程。作用通路主要是破骨细胞的分化（94.12%）。结论 采用分子对接结合网络药理学的方法，从多靶点多途径的角度研究桂枝芍药知母汤治疗类风湿关节炎的药效物质基础及分子机制，为更好的临床用药提供参考和依据。

Objective To predict the active constituents and targets of Guizhi Shaoyao Zhimu Decoction (GSZD) in the treatment of rheumatoid arthritis by using molecular docking and network pharmacology, and to analyze the effect of multi component-multi target-multi pathway combined with the theory of compatibility of TCM prescriptions. Methods The main chemical constituents of nine kinds of Chinese herbal medicines (Cinnamomi Ramulus, Paeoniae Radix Alba, Anemarrhenae Rhizoma, Glycyrrhizae Radix et Rhizoma, Ephedrae Herba, Zingiberis Rhizoma Recens, Atractylodis Macrocephalae Rhizoma, Saposhnikoviae Radix and Aconiti Lateralis Radix Praeparata) were collected from TCMSP, TCM-Datebas@Taiwan and PubChen Compound database. The protein targets to the treatment of rheumatoid arthritis are found through DrugBank and TTD databases and uploaded to the String online database to build the network relationship of protein interaction. Appropriate crystal structures of protein targets were downloaded from PDB database, and molecular docking between compounds and targets was performed by using Discovery studio 4.5.0 software. A drug-compound-target visualization network was constructed by using Cytoscape 3.6.1 software to elucidate the main mechanism of GSZD against rheumatoid arthritis. Results The results of molecular docking showed that there were 316 potential anti-arthritis active components in GSZD, acting on 26 targets, among which MAPK1, ZADH2, P38, AKR1C2, DHODH, CA2, MMP3, MMP9, RANKL, and other proteins were the main targets. Biological function and pathway analysis indicated that the mechanism of GSZD mainly involved in bone absorption (28%), histone kinase activity (20%), peptide tyrosine phosphorylation (20%), prostaglandin metabolism (12%), and other biological processes. The main pathway was osteoclast differentiation (94.12%). Conclusion In this study, molecular docking combined with network pharmacology was used to study the pharmacodynamic material basis and molecular mechanism of GSZD in the treatment of rheumatoid arthritis from the perspective of multi-target and multi-approach, providing reference and basis for better clinical use.

R285.5

国家科技重大专项课题（2018ZX09721004-009-002）