Fragment-based lead discovery using X-ray crystallography
Fragment-based lead discovery using X-ray crystallography
复制标题
DOI：
10.1021/jm0495778
复制
发表时间：
2005-01-27
影响因子：
7.3
通讯作者：
Jhoti, H
中科院分区：
文献类型：
--
作者：
Hartshorn, MJ;Murray, CW;Jhoti, H
片段筛选为发现药物发现项目中的新线索提供了传统筛选的替代方案。本文介绍了一种基于高通量x射线晶体学的碎片筛选方法。该方法适用于5种蛋白（p38 MAP激酶、CDK2、凝血酶、核糖核酸酶A和PTP1B）。所鉴定的片段效力较弱（bbb100 muM），但相对于它们的大小来说是有效的结合剂，因此可能代表着向优质先导化合物进化的合适起点。这些例子表明，一系列分子相互作用（即亲脂性、电荷-电荷、中性氢键）可以驱动片段结合，片段也可以诱导蛋白质运动。我们相信这种方法对于发现针对一系列靶标的新型先导化合物具有很大的潜力，并且伴随的论文说明了如何从本文中描述的片段开始鉴定p38 MAP激酶的先导化合物。
Fragment screening offers an alternative to traditional screening for discovering new leads in drug discovery programs. This paper describes a fragment screening methodology based on high throughput X-ray crystallography. The method is illustrated against five proteins (p38 MAP kinase, CDK2, thrombin, ribonuclease A, and PTP1B). The fragments identified have weak potency (> 100 muM) but are efficient binders relative to their size and may therefore represent suitable starting points for evolution to good quality lead compounds. The examples illustrate that a range of molecular interactions (i.e., lipophilic, charge-charge, neutral hydrogen bonds) can drive fragment binding and also that fragments can induce protein movement. We believe that the method has great potential for the discovery of novel lead compounds against a range of targets, and the companion paper illustrates how lead compounds have been identified for p38 MAP kinase starting from fragments such as those described in this paper.