摘 要
基于结构生物学的药物设计策略是现代药物研发领域的重要方向，旨在通过解析靶标蛋白的三维结构，为药物分子的设计提供精准指导。随着X射线晶体学、核磁共振波谱学和冷冻电镜技术的发展，越来越多的蛋白质结构得以高分辨率解析，这为基于结构的药物设计提供了丰富的数据资源。本研究聚焦于特定疾病相关的关键靶点蛋白，利用多种结构生物学手段获取其精确的空间构象，并结合计算机辅助药物设计方法，构建虚拟筛选模型以寻找潜在的小分子抑制剂。在研究过程中，创新性地引入了动态构象分析与热力学稳定性评估相结合的方式，不仅考虑静态结构特征，还深入探究了蛋白质在生理条件下的运动变化规律及其对配体结合的影响机制。通过对一系列化合物进行活性测试验证，发现多个具有优良生物活性的新颖化合物，其中部分先导化合物展现出良好的成药性和较低的细胞毒性。该研究突破了传统基于单一静态结构设计药物的局限，提出了一种综合考量蛋白质结构动态特性的新策略，在提高药物研发效率和成功率方面具有重要意义，为后续临床前研究奠定了坚实基础。
关键词：基于结构的药物设计；蛋白质动态构象；计算机辅助药物设计；热力学稳定性评估；小分子抑制剂筛选
Abstract
Structure-based drug design strategies represent a critical direction in modern pharmaceutical research, aiming to provide precise guidance for drug molecule design through the elucidation of target protein three-dimensional structures. Advances in X-ray crystallography, nuclear magnetic resonance spectroscopy, and cryo-electron microscopy have enabled the high-resolution determination of an increasing number of protein structures, thereby providing abundant data resources for structure-based drug design. This study focuses on key target proteins associated with specific diseases, employing various structural biology techniques to obtain their precise spatial conformations and integrating computer-aided drug design methods to construct virtual screening models for identifying potential small-molecule inhibitors. During the research process, an innovative approach combining dynamic conformational analysis with thermodynamic stability assessment was introduced, considering not only static structural features but also delving into the movement patterns of proteins under physiological conditions and their impact mechanisms on ligand binding. Through activity testing validation of a series of compounds, multiple novel compounds with excellent biological activity were discovered, some of which exhibit good drug-like properties and low cytotoxicity. This research overcomes the limitations of traditional drug design based on single static structures by proposing a new strategy that comprehensively considers the dynamic characteristics of protein structures, significantly enhancing the efficiency and success rate of drug development and laying a solid foundation for subsequent preclinical studies.
Keywords：Structure-Based Drug Design；Protein Dynamic Conformation；Computer-Aided Drug Design；Thermodynamic Stability Evaluation；Small Molecule Inhibitor Screening
目 录
摘 要 I
Abstract II
引 言 1
第一章 结构生物学基础理论 2
1.1 蛋白质结构解析技术 2
1.2 关键活性位点识别 2
1.3 分子间相互作用原理 3
第二章 靶点选择与验证策略 5
2.1 疾病相关靶点筛选 5
2.2 靶点可药性评估 5
2.3 靶点特异性验证 6
第三章 小分子药物设计方法 8
3.1 基于结构的虚拟筛选 8
3.2 分子对接与优化 8
3.3 成药性预测模型 9
第四章 设计策略的应用实践 10
4.1 抗体药物偶联物设计 10
4.2 酶抑制剂开发案例 10
4.3 新型疫苗研发探索 11
结 论 13
参考文献 14
致 谢 15
