Biomedicine Key Laboratory of Shaanxi Province, College of Life Sciences, Northwest University, Xi'an, 710069, China.
Physical and Chemical Laboratory, Shaanxi Provincial Center for Disease Control and Prevention, Xi'an, 710054, China.
Sci Rep. 2022 May 6;12(1):7430. doi: 10.1038/s41598-022-10769-w.
Eucommia ulmoides Oliver is one of the commonly used traditional Chinese medicines for the treatment of osteoporosis, and iridoid glycosides are considered to be its active ingredients against osteoporosis. This study aims to clarify the chemical components and molecular mechanism of iridoid glycosides of Eucommia ulmoides Oliver in the treatment of osteoporosis by integrating network pharmacology and molecular simulations. The active iridoid glycosides and their potential targets were retrieved from text mining as well as Swiss Target Prediction, TargetNet database, and STITCH databases. At the same time, DisGeNET, GeneCards, and Therapeutic Target Database were used to search for the targets associated with osteoporosis. A protein-protein interaction network was built to analyze the interactions between targets. Then, DAVID bioinformatics resources and R 3.6.3 project were used to carry out Gene Ontology enrichment analysis and Kyoto Encyclopedia of Genes and Genomes pathway analysis. Moreover, interactions between active compounds and potential targets were investigated through molecular docking, molecular dynamic simulation, and binding free energy analysis. The results showed that a total of 12 iridoid glycosides were identified as the active iridoid glycosides of Eucommia ulmoides Oliver in the treatment of osteoporosis. Among them, aucubin, reptoside, geniposide and ajugoside were the core compounds. The enrichment analysis suggested iridoid glycosides of Eucommia ulmoides Oliver prevented osteoporosis mainly through PI3K-Akt signaling pathway, MAPK signaling pathway and Estrogen signaling pathway. Molecular docking results indicated that the 12 iridoid glycosides had good binding ability with 25 hub target proteins, which played a critical role in the treatment of osteoporosis. Molecular dynamic and molecular mechanics Poisson-Boltzmann surface area results revealed these compounds showed stable binding to the active sites of the target proteins during the simulations. In conclusion, our research demonstrated that iridoid glycosides of Eucommia ulmoides Oliver in the treatment of osteoporosis involved a multi-component, multi-target and multi-pathway mechanism, which provided new suggestions and theoretical support for treating osteoporosis.
杜仲是治疗骨质疏松症的常用中药之一，其环烯醚萜苷类成分被认为是治疗骨质疏松症的活性成分。本研究旨在通过整合网络药理学和分子模拟技术，阐明杜仲环烯醚萜苷类化合物治疗骨质疏松症的化学成分和分子机制。从文本挖掘以及 SwissTargetPrediction、TargetNet 数据库和 STITCH 数据库中检索到活性环烯醚萜苷及其潜在靶点。同时，使用 DisGeNET、GeneCards 和 TherapeuticTargetDatabase 搜索与骨质疏松症相关的靶点。构建蛋白质-蛋白质相互作用网络分析靶点之间的相互作用。然后，使用 DAVID 生物信息学资源和 R 3.6.3 项目进行基因本体论富集分析和京都基因与基因组百科全书通路分析。此外，通过分子对接、分子动力学模拟和结合自由能分析研究活性化合物与潜在靶点之间的相互作用。结果表明，共鉴定出 12 种杜仲环烯醚萜苷类化合物为治疗骨质疏松症的活性成分。其中，梓醇、京尼平苷酸、栀子苷和筋骨草苷为核心化合物。富集分析表明，杜仲环烯醚萜苷类化合物预防骨质疏松症主要通过 PI3K-Akt 信号通路、MAPK 信号通路和雌激素信号通路。分子对接结果表明，12 种环烯醚萜苷类化合物与 25 个关键靶蛋白具有良好的结合能力，在治疗骨质疏松症中发挥着重要作用。分子动力学和分子力学泊松-玻尔兹曼表面面积结果表明，这些化合物在模拟过程中能够稳定地结合到靶蛋白的活性部位。综上所述，本研究表明，杜仲环烯醚萜苷类化合物治疗骨质疏松症涉及多成分、多靶点和多通路的机制，为治疗骨质疏松症提供了新的思路和理论支持。
