Division of Medicinal Chemistry, Faculty of Sciences, Amsterdam Institute for Molecules, Medicines and Systems (AIMMS), VU University Amsterdam, De Boelelaan 1083, 1081 HV Amsterdam, The Netherlands.
Drug Discov Today. 2013 Apr;18(7-8):323-30. doi: 10.1016/j.drudis.2012.12.003. Epub 2012 Dec 22.
Smaller stones with a wide variety of colors make a higher resolution mosaic. In much the same way, smaller chemical entities that are structurally diverse are better able to interrogate protein binding sites. This feature article describes the construction of a diverse fragment library and an analysis of the screening of six representative protein targets belonging to three diverse target classes (G protein-coupled receptors ADRB2, H1R, H3R, and H4R, the ligand-gated ion channel 5-HT3R, and the kinase PKA) using chemogenomics approaches. The integration of experimentally determined bioaffinity profiles across related and unrelated protein targets and chemogenomics analysis of fragment binding and protein structure allow the identification of: (i) unexpected similarities and differences in ligand binding properties, and (ii) subtle ligand affinity and selectivity cliffs. With a wealth of fragment screening data being generated in industry and academia, such approaches will contribute to a more detailed structural understanding of ligand-protein interactions.
较小的石头具有各种颜色，可以形成更高分辨率的马赛克。同样，结构多样的较小化学实体更能够探测蛋白质结合位点。这篇专题文章描述了多样化的片段文库的构建，以及使用化学生物学方法对六个具有代表性的属于三个不同靶类别的蛋白质靶标（G 蛋白偶联受体 ADRB2、H1R、H3R 和 H4R、配体门控离子通道 5-HT3R 和激酶 PKA）进行筛选的分析。通过对相关和不相关的蛋白质靶标进行实验确定的生物亲和力谱的整合，以及对片段结合和蛋白质结构的化学生物学分析，可以确定：（i）配体结合特性的意外相似性和差异性，以及（ii）微妙的配体亲和力和选择性悬崖。随着工业界和学术界产生大量的片段筛选数据，这种方法将有助于更详细地了解配体-蛋白质相互作用的结构。
