Phongphithakchai Atthaphong, Tedasen Aman, Netphakdee Ratana, Leelawattana Rattana, Srithongkul Thatsaphan, Raksasuk Sukit, Huang Jason C, Chatatikun Moragot
Nephrology Unit, Division of Internal Medicine, Faculty of Medicine, Prince of Songkla University, Songkhla 90110, Thailand.
Department of Medical Technology, School of Allied Health Sciences, Walailak University, Nakhon Si Thammarat 80160, Thailand.
Life (Basel). 2025 Mar 11;15(3):437. doi: 10.3390/life15030437.
Chronic kidney disease (CKD) involves inflammation, oxidative stress, and fibrosis, leading to renal dysfunction. Dapagliflozin, an SGLT2 inhibitor, shows renoprotective effects beyond glucose control, but its precise molecular mechanisms remain unclear. This study utilizes network pharmacology and molecular docking to elucidate its multi-target effects in CKD. Dapagliflozin's SMILES structure was analyzed for ADMET properties. Potential targets were identified via SwissTargetPrediction, GeneCards, and SEA, and common CKD-related targets were determined. A protein-protein interaction (PPI) network was constructed, and key pathways were identified using GO and KEGG enrichment analyses. Molecular docking was conducted to validate dapagliflozin's binding affinities with hub proteins. A total of 208 common targets were identified, including EGFR, GSK3β, and IL-6. GO and KEGG analyses highlighted key pathways, such as PI3K-Akt, MAPK, and AGE-RAGE, involved in inflammation, oxidative stress, and metabolic regulation. Molecular docking confirmed strong binding affinities with EGFR (-8.42 kcal/mol), GSK3β (-7.70 kcal/mol), and IL-6 (-6.83 kcal/mol). Dapagliflozin exhibits multi-target therapeutic potential in CKD by modulating inflammation, oxidative stress, and metabolic pathways. This integrative approach enhances the understanding of its mechanisms, supporting future experimental validation and clinical application in CKD management.
慢性肾脏病（CKD）涉及炎症、氧化应激和纤维化，导致肾功能障碍。达格列净是一种钠-葡萄糖协同转运蛋白2（SGLT2）抑制剂，除了控制血糖外还显示出肾脏保护作用，但其确切的分子机制仍不清楚。本研究利用网络药理学和分子对接来阐明其在CKD中的多靶点作用。分析了达格列净的SMILES结构的药物代谢动力学（ADMET）特性。通过瑞士靶点预测、基因卡片和SEA数据库确定潜在靶点，并确定常见的CKD相关靶点。构建了蛋白质-蛋白质相互作用（PPI）网络，并使用基因本体（GO）和京都基因与基因组百科全书（KEGG）富集分析确定关键通路。进行分子对接以验证达格列净与枢纽蛋白的结合亲和力。共鉴定出208个常见靶点，包括表皮生长因子受体（EGFR）、糖原合成酶激酶3β（GSK3β）和白细胞介素-6（IL-6）。GO和KEGG分析突出了参与炎症、氧化应激和代谢调节的关键通路，如磷脂酰肌醇-3激酶（PI3K）-蛋白激酶B（Akt）、丝裂原活化蛋白激酶（MAPK）和晚期糖基化终末产物受体（AGE-RAGE）通路。分子对接证实达格列净与EGFR（-8.42千卡/摩尔）、GSK3β（-7.70千卡/摩尔）和IL-6（-6.83千卡/摩尔）具有很强的结合亲和力。达格列净通过调节炎症、氧化应激和代谢途径在CKD中展现出多靶点治疗潜力。这种综合方法增进了对其机制的理解，为未来在CKD管理中的实验验证和临床应用提供了支持。
