Fejzo J, Lepre C A, Peng J W, Bemis G W, Murcko M A, Moore J M
Vertex Pharmaceuticals Incorporated 130 Waverly Street, Cambridge, MA 02139-4242, USA.
Chem Biol. 1999 Oct;6(10):755-69. doi: 10.1016/s1074-5521(00)80022-8.
Recently, it has been shown that nuclear magnetic resonance (NMR) may be used to identify ligands that bind to low molecular weight protein drug targets. Recognizing the utility of NMR as a very sensitive method for detecting binding, we have focused on developing alternative approaches that are applicable to larger molecular weight drug targets and do not require isotopic labeling.
A new method for lead generation (SHAPES) is described that uses NMR to detect binding of a limited but diverse library of small molecules to a potential drug target. The compound scaffolds are derived from shapes most commonly found in known therapeutic agents. NMR detection of low (microM-mM) affinity binding is achieved using either differential line broadening or transferred NOE (nuclear Overhauser effect) NMR techniques.
The SHAPES method for lead generation by NMR is useful for identifying potential lead classes of drugs early in a drug design program, and is easily integrated with other discovery tools such as virtual screening, high-throughput screening and combinatorial chemistry.
最近研究表明，核磁共振（NMR）可用于识别与低分子量蛋白质药物靶点结合的配体。认识到NMR作为一种检测结合的非常灵敏的方法的实用性后，我们专注于开发适用于更大分子量药物靶点且不需要同位素标记的替代方法。
描述了一种新的先导化合物生成方法（SHAPES），该方法利用NMR检测有限但多样的小分子文库与潜在药物靶点的结合。化合物支架源自已知治疗剂中最常见的形状。使用差分线展宽或转移核Overhauser效应（NOE）NMR技术可实现低（微摩尔-毫摩尔）亲和力结合的NMR检测。
通过NMR生成先导化合物的SHAPES方法有助于在药物设计项目早期识别潜在的先导药物类别，并且很容易与虚拟筛选、高通量筛选和组合化学等其他发现工具相结合。
