Cao Jin, Wang Dayong, Yuan Jianhua, Hu Fenggen, Wu Zhen
Department of Orthopedics, First People's Hospital of Linping District, Hangzhou, China.
Department of Orthopedics, Tongde Hospital of Zhejiang Province, Hangzhou, China.
Comput Methods Biomech Biomed Engin. 2024 Jan-Mar;27(2):251-265. doi: 10.1080/10255842.2023.2268232. Epub 2024 Jan 18.
In this study, the active ingredients of 15 Chinese herbal medicines of Duhuo Jisheng Decoction and their corresponding targets were obtained from the Traditional Chinese Medicine Systems Pharmacology (TCMSP) database. The microarray data of Osteoarthritis (OA) were obtained through the GEO database for differential analysis and then a drug target-OA-related gene protein-protein interaction (PPI) network was established. The potential targets of Duhuo Jisheng Decoction in the treatment of OA were acquired by intersecting the OA-associated genes with the target genes of active ingredients. Random walk with restart (RWR) analysis of PPI networks was performed using potential targets as seed, and the top 50 genes of affinity coefficients were used as key action genes of Duhuo Jisheng Decoction in the treatment of OA. A drug-active ingredient-gene interaction network was established. AKT1, a key target of Duhuo Jisheng Decoction in the treatment of OA, was obtained by topological analysis of the gene interaction network. Molecular docking and molecular dynamics verified the binding of AKT1 to its corresponding drug active ingredients. CETSA assay demonstrated that the combination of luteolin and AKT1 increased the stability of AKT1, and the combination efficiency was high. In conclusion, the molecular mechanism of Duhuo Jisheng Decoction in treating OA featured by multiple components, targets, and pathways had been further investigated in this study, which is of significance for discovering as well as developing new drugs for this disease. The findings can also offer personalized diagnosis and treatment strategies for patients with OA in clinical practice.
本研究从中药系统药理学（TCMSP）数据库获取独活寄生汤15味中药的活性成分及其相应靶点。通过GEO数据库获取骨关节炎（OA）的微阵列数据进行差异分析，进而构建药物靶点 - OA相关基因蛋白质 - 蛋白质相互作用（PPI）网络。通过将OA相关基因与活性成分的靶点基因进行交集分析，获得独活寄生汤治疗OA的潜在靶点。以潜在靶点为种子对PPI网络进行重启随机游走（RWR）分析，将亲和系数排名前50的基因作为独活寄生汤治疗OA的关键作用基因，构建药物 - 活性成分 - 基因相互作用网络。通过对基因相互作用网络的拓扑分析，获得独活寄生汤治疗OA的关键靶点AKT1。分子对接和分子动力学验证了AKT1与其相应药物活性成分的结合。CETSA实验表明木犀草素与AKT1的结合增加了AKT1的稳定性，且结合效率较高。综上所述，本研究进一步探究了独活寄生汤治疗OA多成分、多靶点、多途径的分子机制，对该病新药的发现和开发具有重要意义。研究结果也可为临床OA患者提供个性化诊疗策略。
