网络毒理学与分子对接技术分析松弛素信号通路在利塞膦酸钠致颌骨骨坏死中的作用OA
Analysis of the role of the relaxin signaling pathway in risedronate sodium-induced osteonecrosis of the jaw through network toxicology and molecular docking techniques
目的 通过网络毒理学和分子对接方法,探讨利塞膦酸钠导致颌骨坏死(ONJ)的潜在机制.方法 基于Genecards、MalaCards、比较毒物基因组学数据库和TargetNet数据库筛选利塞膦酸钠与ONJ的潜在靶点,利用GeneMania在线平台构建蛋白质-蛋白质互作网络获取潜在核心靶点.通过降维聚类和元路径分析,筛选核心调控靶点.采用基因本体论(GO)和京都基因与基因组百科全书(KEGG)富集分析识别核心靶点所富集的关键通路.使用PubChem和布鲁克海文蛋白质数据库中获取利塞膦酸钠结构文件与核心调控靶点蛋白 3D结构,通过CB-Dock2平台进行分子对接.结果 共鉴定出15个ONJ与利塞膦酸钠的共同靶点.通过蛋白质-蛋白质互作网络分析获得34个潜在核心靶点,降维聚类后获得18个核心靶点.GO和KEGG结果显示,核心靶点主要富集于松弛素信号通路、雌激素信号通路和精氨酸生物合成.元路径分析进一步确认了4个核心调控靶点(NOS1、NOS2、NOS3、SRC),且这些靶点富集于松弛素信号通路.分子对接结果显示,利塞膦酸钠与核心调控靶点具有良好的结合能力.结论 研究通过元路径分析整合降维聚类和分子对接方法,揭示了利塞膦酸钠可通过NOS1、NOS2、NOS3和SRC激活松弛素信号通路诱发ONJ的潜在机制.这一发现为双膦酸盐类药物的骨毒性机制研究提供了全新、多维度分析范式,为后续细胞和动物实验提供了理论基础.
Objective To explore the potential mechanism by which risedronate sodium induces os-teonecrosis of the jaw(ONJ)using network toxicology and molecular docking methods.Methods Poten-tial targets of risedronate sodium and ONJ were screened based on the Genecards,MalaCards,Com-parative Toxicogenomics Database,and TargetNet databases.The GeneMania online platform was uti-lized to construct a protein-protein interaction network to obtain potential core targets.Core regulatory targets were screened through dimensionality reduction clustering and meta-path analysis.Gene ontol-ogy(GO)and Kyoto Encyclopedia of Genes and Genomes(KEGG)enrichment analyses were con-ducted to identify key pathways enriched by the core targets.The structural files of risedronate sodium and the 3D structures of core regulatory target proteins were obtained from PubChem and the Brookhaven Protein Database,respectively,and molecular docking was performed using the CB-Dock2 platform.Results A total of 15 common targets between ONJ and risedronate sodium were identified.Through PPI network analysis,34 potential core targets were obtained,and 18 core targets were identified after dimensionality reduction clustering.GO and KEGG results revealed that the core targets were mainly enriched in the relaxin signaling pathway,estrogen signaling pathway,and arginine biosynthesis.Meta-path analysis further confirmed four core regulatory targets(NOS1,NOS2,NOS3,and SRC),which were enriched in the relaxin signaling pathway.Molecular docking results demonstrated that risedronate sodium had good binding ability to the core regulatory targets.Conclusion By integrating dimensionality reduction clustering and molecular docking methods through meta-path analysis,this study revealed the potential mechanism by which risedronate sodium can activate the relaxin signaling pathway via NOS1,NOS2,NOS3,and SRC to induce ONJ.This finding provides a novel,multidimensional analytical paradigm for studying the bone toxicity mecha-nisms of bisphosphonates and offers a theoretical basis for subsequent cellular and animal experiments.
梁艺馨;林红晓;张伟;石晓琦
江苏省连云港市第一人民医院骨质疏松科,江苏连云港,222061江苏省连云港市第一人民医院骨质疏松科,江苏连云港,222061江苏省连云港市第一人民医院骨质疏松科,江苏连云港,222061江苏省连云港市第一人民医院骨质疏松科,江苏连云港,222061
医药卫生
利塞膦酸钠双膦酸盐颌骨坏死网络毒理学分子对接松弛素信号通路一氧化氮合酶蛋白质-蛋白质互作网络
risedronate sodiumbisphosphonateosteonecrosis of the jawnetwork toxicologymolecular dockingrelaxin signaling pathwaynitric oxide synthaseprotein-protein interaction network
《实用临床医药杂志》 2026 (5)
40-47,8
2024年连云港市卫生健康面上科技项目(202406)
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