Weigelt Johan, Wikström Mats, Schultz Johan, van Dongen Maria J P
Biovitrum, Structural Chemistry, Stockholm, S-112 76, Sweden.
Comb Chem High Throughput Screen. 2002 Dec;5(8):623-30. doi: 10.2174/1386207023329978.
NMR based screening has become an important tool in the pharmaceutical industry. Methods that provide information on the location of small molecule binding sites on the surface of a drug target (e. g. SAR-by-NMR and related techniques) are of particular interest. In order to extend the applicability of such techniques to drug targets of higher molecular weight, selective labeling strategies may be employed. Dual-amino acid selective labeling and site directed non-native amino acid replacement (SNAAR) allow for the selective detection of NMR resonances of a specific amino acid residue. This results in significantly reduced spectral complexity, which not only enables application to higher molecular weight systems, but also eliminates the need for sequential resonance assignment in order to identify the binding site. Regio-selective (or segmental) labeling of an entire protein domain of a multi domain protein may also be achieved. Labeling only a selected part of a multi domain protein (e. g. a catalytic or ligand binding domain) is an attractive way to simplify the spectral interpretation without disturbing the system under study.
基于核磁共振的筛选已成为制药行业的一项重要工具。能够提供小分子在药物靶点表面结合位点位置信息的方法（例如基于核磁共振的药物结构活性关系研究及相关技术）尤其受到关注。为了将此类技术的适用性扩展到更高分子量的药物靶点，可采用选择性标记策略。双氨基酸选择性标记和定点非天然氨基酸置换（SNAAR）能够选择性地检测特定氨基酸残基的核磁共振信号。这显著降低了光谱复杂性，不仅使得该技术能够应用于更高分子量的体系，而且无需进行顺序共振归属即可识别结合位点。还可以实现对多结构域蛋白的整个蛋白结构域进行区域选择性（或片段性）标记。仅标记多结构域蛋白的选定部分（例如催化或配体结合结构域）是一种在不干扰所研究体系的情况下简化光谱解读的有效方法。
