Spectroscopy and NMR Unit, Structural Biology and Biocomputing Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
Curr Top Med Chem. 2011;11(1):43-67. doi: 10.2174/156802611793611887.
Over the past three decades nuclear magnetic resonance spectroscopy has been developed into a mature technique for the characterization of interactions of small molecule ligands with their corresponding protein and nucleic acid receptors. In fact, a significant number of industrial and academic laboratories employ NMR for screening small molecule compound collections for binding to defined macromolecular targets, thus potentially providing initial, low affinity hits for a fragment-based approach in the drug discovery process. NMR is also applied to interrogate hits obtained by high throughput screening using biochemical assays and by virtual screening methods, for their ability to physically interact with the target receptor. In favorable cases a variety of NMR-based methods can also provide essential information to validate the hit, rank the different hits according to affinity, and to structurally analyze the ligand-target complex, thus providing essential information for structure-based optimization and medicinal chemistry. In this review a comprehensive overview of the large variety of NMR methods to study interactions between small molecule ligands and macromolecular receptors is provided, summarizing the physico-chemical bases of the different receptor- and ligand-observed experiments. The application of these methods for compound library screening and hit validation, with special emphasis on their contribution to fragment-based drug discovery strategies, is illustrated by recent examples selected from the literature and work in my laboratory.
在过去的三十年中，核磁共振波谱已发展成为一种成熟的技术，可用于表征小分子配体与其相应的蛋白质和核酸受体的相互作用。事实上，许多工业和学术实验室都采用 NMR 技术筛选与特定大分子靶标结合的小分子化合物库，从而为药物发现过程中的基于片段的方法提供初步的低亲和力命中。NMR 还用于通过生化测定和虚拟筛选方法来检测高通量筛选获得的命中，以研究它们与靶受体相互作用的能力。在有利的情况下，各种基于 NMR 的方法还可以提供验证命中所需的重要信息，根据亲和力对不同的命中进行排序，并对配体-靶复合物进行结构分析，从而为基于结构的优化和药物化学提供重要信息。在这篇综述中，全面概述了用于研究小分子配体和大分子受体之间相互作用的大量 NMR 方法，总结了不同受体观察和配体观察实验的物理化学基础。通过文献中的最新实例和我实验室的工作，说明了这些方法在化合物库筛选和命中验证中的应用，特别强调了它们对基于片段的药物发现策略的贡献。
