Exploring the Molecular Mechanisms of SB216763 in the Therapeutic Intervention of Pulmonary Fibrosis Based on Macrophage Functional Plasticity‌

IF 2.7 4区医学 Q3 PHARMACOLOGY & PHARMACY

Fundamental & Clinical Pharmacology Pub Date : 2026-08-18 DOI:10.1111/fcp.70111

Yunuo Zhou, Pei Zhou, Jianhong Qi

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引用次数: 0

Abstract

Background

SB216763 has demonstrated efficacy in treating pulmonary fibrosis in animal models, but its underlying mechanisms remain poorly understood. This study used network pharmacology, molecular docking, and molecular dynamics simulations to explore the molecular mechanisms by which SB216763 exerts therapeutic effects on pulmonary fibrosis.

Methods

The targets of SB216763 were screened using the PharmMapper database, while pulmonary fibrosis-related targets were obtained from GeneCards and OMIM databases. A Venn diagram generated from these datasets highlighted overlapping targets. Protein–protein interaction networks were constructed using the STRING database and Cytoscape software to assess target importance. GO and KEGG enrichment analyses using the Metascape database revealed relevant biological functions and signaling pathways of SB216763 in the treatment of pulmonary fibrosis. Molecular docking investigated the binding affinity and binding mode of SB216763 with GSK-3β. Molecular dynamics simulations further confirmed the stability of the complex formed by SB216763 and GSK-3β. Finally, Western blotting, Griess assays, and ELISA were employed to validate the effect of SB216763 on macrophage functional plasticity in pulmonary fibrosis.

Results

Network pharmacology analysis identified the following three key targets of SB216763 in pulmonary fibrosis: AKT1, GSK3B, and TGFBR1, along with the PI3K-AKT signaling pathway. Molecular docking and dynamics simulations revealed that SB216763 primarily interacts with GSK-3β through hydrogen bonds and hydrophobic interactions. In vitro validation demonstrated significant anti-inflammatory and antifibrotic effects of SB216763. Additionally, SB216763 exhibited good safety in macrophages.

Conclusions

This study provided new insights into the mechanisms of SB216763 in the treatment of pulmonary fibrosis.

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基于巨噬细胞功能可塑性的SB216763干预肺纤维化治疗的分子机制探讨

背景SB216763在动物模型中已显示出治疗肺纤维化的疗效，但其潜在机制尚不清楚。本研究采用网络药理学、分子对接、分子动力学模拟等方法，探讨SB216763治疗肺纤维化的分子机制。方法利用PharmMapper数据库筛选SB216763的靶点，利用GeneCards和OMIM数据库筛选肺纤维化相关靶点。从这些数据集生成的维恩图突出了重叠的目标。利用STRING数据库和Cytoscape软件构建蛋白-蛋白相互作用网络来评估靶点的重要性。利用metscape数据库进行GO和KEGG富集分析，揭示了SB216763在治疗肺纤维化中的相关生物学功能和信号通路。分子对接研究SB216763与GSK-3β的结合亲和力和结合方式。分子动力学模拟进一步证实了SB216763与GSK-3β形成的配合物的稳定性。最后，采用Western blotting、Griess法和ELISA法验证SB216763对肺纤维化巨噬细胞功能可塑性的影响。结果网络药理学分析确定了SB216763在肺纤维化中的三个关键靶点：AKT1、GSK3B和TGFBR1，以及PI3K-AKT信号通路。分子对接和动力学模拟表明，SB216763主要通过氢键和疏水相互作用与GSK-3β相互作用。体外验证表明SB216763具有明显的抗炎和抗纤维化作用。此外，SB216763在巨噬细胞中表现出良好的安全性。本研究为SB216763治疗肺纤维化的机制提供了新的见解。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Fundamental & Clinical Pharmacology 医学-药学

CiteScore

5.30

自引率

6.90%

发文量

111

审稿时长

6-12 weeks

期刊介绍： Fundamental & Clinical Pharmacology publishes reports describing important and novel developments in fundamental as well as clinical research relevant to drug therapy. Original articles, short communications and reviews are published on all aspects of experimental and clinical pharmacology including: Antimicrobial, Antiviral Agents Autonomic Pharmacology Cardiovascular Pharmacology Cellular Pharmacology Clinical Trials Endocrinopharmacology Gene Therapy Inflammation, Immunopharmacology Lipids, Atherosclerosis Liver and G-I Tract Pharmacology Metabolism, Pharmacokinetics Neuropharmacology Neuropsychopharmacology Oncopharmacology Pediatric Pharmacology Development Pharmacoeconomics Pharmacoepidemiology Pharmacogenetics, Pharmacogenomics Pharmacovigilance Pulmonary Pharmacology Receptors, Signal Transduction Renal Pharmacology Thrombosis and Hemostasis Toxicopharmacology Clinical research, including clinical studies and clinical trials, may cover disciplines such as pharmacokinetics, pharmacodynamics, pharmacovigilance, pharmacoepidemiology, pharmacogenomics and pharmacoeconomics. Basic research articles from fields such as physiology and molecular biology which contribute to an understanding of drug therapy are also welcomed.