Application of fragment screening and fragment linking to the discovery of novel thrombin inhibitors
Application of fragment screening and fragment linking to the discovery of novel thrombin inhibitors
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DOI：
10.1021/jm050850v
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发表时间：
2006-02-23
影响因子：
7.3
通讯作者：
van Montfort, RLM
中科院分区：
文献类型：
--
作者：
Howard, N;Abell, C;van Montfort, RLM
片段的筛选是用于鉴定治疗靶点的先导物的高通量筛选的替代方法。使用丝氨酸蛋白酶凝血酶的蛋白质晶体的X射线晶体学筛选已经发现了片段命中。片段库的设计避免了任何有先例的、强基本功能。筛选命中包括一种新的配体（3），除了与S1口袋结合的较小片段外，其仅与S2-S4口袋结合。这些蛋白质-配体复合物的结构。将两个这样的片段连接在一起并合成更大的药物大小的化合物的化学策略导致有效鉴定具有纳摩尔效力的杂合抑制剂（例如，7，IC50 = 3.7 nM）。这些有效的配体占据与先前描述的肽抑制剂相同的活性位点区域，同时具有非常不同的化学结构。
The screening of fragments is an alternative approach to high-throughput screening for the identification of leads for therapeutic targets. Fragment hits have been discovered using X-ray crystallographic screening of protein crystals of the serine protease enzyme thrombin. The fragment library was designed to avoid any well-precedented, strongly basic functionality. Screening hits included a novel ligand (3), which binds exclusively to the S2-S4 pocket, in addition to smaller fragments which bind to the S1 pocket. The structure of these protein-ligand complexes are presented. A chemistry strategy to link two such fragments together and to synthesize larger drug-sized compounds resulted in the efficient identification of hybrid inhibitors with nanomolar potency (e.g., 7, IC50 = 3.7 nM). These potent ligands occupy the same area of the active site as previously described peptidic inhibitors, while having very different chemical architecture.