基于片段的先导化合物发现中的核磁应用

摘要/Abstract

摘要：

基于片段的药物筛选与设计在过去10年开始出现并获得了重要的应用，数十种基于片段的药物已经进入临床测试期. 源于靶标蛋白和小分子片段本质上的弱相互作用，现代核磁技术在其中发挥着无可替代的作用. 该文简略介绍了核磁片段筛选的基本流程和重要概念，包括靶标蛋白的选择、片段库的设计、质量控制和重要的核磁筛选技术. 在后续的基于片段的先导化合物发现阶段，阐述了核磁新技术的基本理论框架，包括化学位移扰动、分子间NOE、残留偶极耦合和顺磁标记等方法，以及这些新技术在靶标/配基复合体结构研究中的实际应用，穿插演示了片段组装的基本思路和成功案例.

关键词: 核磁共振（NMR）, 基于片段的先导化合物发现, 片段增长, 片段连接, STD, WaterLOGSY

Abstract:

The fragment based drug screening and design emerged in the past decade, and has gained important applications. Many fragmentderived drugs have entered clinical trials. Probing the weak interactions between the target protein and small molecule fragments Modern NMR techniques play a vital role in fragment based lead discovery. In this article, the basic procedures of NMR fragment screening and the relevant key concepts (i.e., target validation, fragment library design, quality control and prevailing NMR fragment screening techniques) were first introduced. The theoretical framework of the NMR techniques commonly used in fragment based lead discovery stage, including chemical shift perturbation, intermolecular NOE, residual dipolar coupling and paramagnetic spin label etc., were also reviewed. Examples were given to show how these techniques can be used to resolve the structure of target/ligand complexs. Strategies of fragment growth, linking and merging were also discussed.

Key words: NMR, fragment based lead discovery, fragment growth, fragment linking, STD, water-LOGSY

中图分类号:

O482.53

阮科, 高佳, 马荣声. 基于片段的先导化合物发现中的核磁应用[J]. 波谱学杂志, 2012, 29(2): 163-181.

RUAN Ke, GAO Jia, MA Rong-Sheng. NMR in Fragment Based Lead Discovery[J]. Chinese Journal of Magnetic Resonance, 2012, 29(2): 163-181.

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