Baggio Carlo, Cerofolini Linda, Fragai Marco, Luchinat Claudio, Pellecchia Maurizio
Division of Biomedical Sciences, School of Medicine, University of California-Riverside, Riverside, California 92521, United States.
Magnetic Resonance Center (CERM), University of Florence and Consorzio Interuniversitario Risonanze Magnetiche di Metallo Proteine (CIRMMP), Via L. Sacconi 6, 50019 Sesto Fiorentino, Italy.
ACS Med Chem Lett. 2018 Jan 17;9(2):137-142. doi: 10.1021/acsmedchemlett.7b00483. eCollection 2018 Feb 8.
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.
我们最近提出了一种基于聚焦位置扫描文库生物物理筛选的新型药物发现方法，其中文库的每个元素都包含针对给定靶点或靶点类别的共同结合部分。在本信函中，我们报告了将该方法应用于含金属蛋白靶点的情况。在我们的实施方案中，我们首先衍生了一个聚焦位置扫描组合文库（约100,000种化合物），其中文库的每个元素在C端都含有金属螯合部分异羟肟酸。通过溶液中的核磁共振光谱对该文库进行筛选，从而鉴定出了针对基质金属蛋白酶-12的新型选择性化合物系列。数据表明，我们的通用方法，或许使用其他金属螯合剂或其他初始结合片段来应用，可能在衍生针对金属酶的新型选择性药物方面非常有效。
