|
| 噻吩[3,2-c]吡唑-3胺类GSK-3β抑制剂的3D-QSAR、分子对接及分子动力学研究 |
| 3D-QSAR, Molecular Docking, and Molecular Dynamics Studies of Thieno[3,2-c]pyrazol-3-amine Derivatives as GSK-3β Inhibitors |
| 投稿时间：2025-12-01 修订日期：2025-12-26 |
| DOI： |
| 中文关键词: 噻吩[3,2-c]吡唑-3胺衍生物 糖原合成酶激酶3β 3D-QSAR 分子对接 ADMET 分子动力学 |
| 英文关键词:Thieno[3,2-c]pyrazol-3-amine derivatives GSK-3β 3D-QSAR Molecular docking ADMET Molecular dynamics |
| 基金项目:国家自然科学基金（编号：82104171）、山西省自然科学基金（编号：20210302124564）、山西省高等学校科技创新项目（编号：2021L228）、山西医科大学省级博士启动基金（编号：SD2021）及山西医科大学博士启动基金（编号：XD2031） |
|
| 摘要点击次数: 16 |
| 全文下载次数: 0 |
| 中文摘要: |
| 糖原合成酶激酶3β(GSK-3β)是阿尔茨海默病药物研发领域的核心靶点。本文选取近期报道的一系列噻吩[3,2-c]吡唑-3胺类GSK-3β抑制剂作为研究对象,开展三维定量构效关系(3D-QSAR)分析。其中,比较分子场分析模型(CoMFA：q2=0.595,ONC=6,r2=0.957)和比较分子相似性指数分析模型(CoMSIA：q2=0.667,ONC=6,r2=0.958)具有良好的预测能力。基于所构建的3D-QSAR模型构效关系分析,本文设计了128个新型化合物。经活性预测发现,其中10个化合物在CoMFA和CoMSIA模型中的预测活性均优于参考分子28(数据集中活性最高),86个化合物在单一模型中的预测活性优于参考分子28。通过ADMET预测和分子对接进一步筛选获得4个与GSK-3β蛋白结合自由能高、合成可行性高、低毒的化合物(a48、a88、a89和a96)。分子动力学模拟结果显示,4个化合物与GSK-3β蛋白形成的复合物结合构象稳定；结合自由能分解进一步表明,与关键氨基酸残基ILE62、PHE67、VAL70、ALA83、LEU132、TYR134、THR138和LEU188形成的疏水相互作用在配体与GSK-3β的结合过程中发挥重要作用。综上,本研究为新型噻吩[3,2-c]吡唑-3胺类GSK3β抑制剂的设计提供理论依据。 |
| 英文摘要: |
| Glycogen synthase kinase 3β (GSK-3β) is a core therapeutic target for Alzheimer’s disease (AD) drug development. This study selected a series of thieno[3,2-c]pyrazol-3-amine-based GSK-3β inhibitors to perform 3D-QSAR analyses. The resulting models, comparative molecular field analysis (CoMFA: q2=0.595, ONC=6, r2=0.957) and comparative molecular similarity index analysis (CoMSIA: q2=0.667, ONC=6, r2=0.958), exhibited a high level of predictive accuracy. Guided by 3D-QSAR analyses, 128 new compounds were designed. Activity prediction revealed 10 compounds showed better activity than the most active Compound 28 in the dataset in both models, and 86 in either. After molecular ADMET prediction and docking, 4 compounds (a48, a88, a89, a96) were obtained with high GSK-3β binding free energy, synthetic feasibility and low toxicity. Molecular dynamics showed stable binding conformations of their complexes with GSK-3β; further binding free energy decomposition analysis indicated that the hydrophobic interactions formed with key amino acid residues (ILE62, PHE67, VAL70, ALA83, LEU132, TYR134, THR138, and LEU188) play a crucial role in the binding process between the ligand and GSK-3β. This study lays a theoretical foundation for the design of novel thieno[3,2-c]pyrazol-3-amine derivatives as GSK-3β inhibitors. |
| 查看/发表评论 下载PDF阅读器 |
| 关闭 |
|
|
|
京公网安备11010802047317号