We have recently proposed a novel drug discovery approach based on biophysical screening of focused positional scanning libraries in which each element of the library contained a common binding moiety for the given target or class of targets. In this Letter, we report on the implementation of this approach to target metal containing proteins. In our implementation, we first derived a focused positional scanning combinatorial library of peptide mimetics (of approximately 100,000 compounds) in which each element of the library contained the metal-chelating moiety hydroxamic acid at the C-terminal. Screening of this library by nuclear magnetic resonance spectroscopy in solution allowed the identification of a novel and selective compound series targeting MMP-12. The data supported that our general approach, perhaps applied using other metal chelating agents or other initial binding fragments, may result very effective in deriving novel and selective agents against metalloenzyme.

中文翻译：

---

NMR HTS用于鉴定金属酶的有效和选择性抑制剂

我们最近提出了一种基于聚焦位置扫描文库的生物物理筛选的新颖药物发现方法，其中该文库的每个元素都包含给定靶标或靶标类别的公共结合部分。在这封信中，我们报告了这种针对目标金属蛋白的方法的实施情况。在我们的实现中，我们首先导出了肽模拟物（约100,000种化合物）的集中位置扫描组合库，其中该库的每个元素在C端均包含金属螯合部分异羟肟酸。通过在溶液中的核磁共振波谱筛选该文库，可以鉴定靶向MMP-12的新型选择性化合物系列。数据支持我们的一般方法，