Structural insights into binding of inhibitors to soluble epoxide hydrolase gained by fragment screening and X-ray crystallography
Structural insights into binding of inhibitors to soluble epoxide hydrolase gained by fragment screening and X-ray crystallography
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DOI：
10.1016/j.bmc.2014.03.001
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发表时间：
2014-04-15
影响因子：
3.5
通讯作者：
Tanabe, Eiki
中科院分区：
文献类型：
--
作者：
Amano, Yasushi;Yamaguchi, Tomohiko;Tanabe, Eiki
可溶性环氧化物水解酶 (sEH) 是花生四烯酸级联的组成部分，是高血压或炎症治疗的候选靶点。尽管有许多 sEH 抑制剂可用，但它们的支架在结构上并不多样化，并且对其与 sEH 的特定相互作用的了解有限。为了获得有关蛋白质-配体相互作用的详细结构信息，我们对 sEH 进行了片段筛选，使用高通量 X 射线晶体学分析片段，并以高分辨率确定了 126 个片段结合结构。氨基噻唑和苯并咪唑衍生物被认为是能够以良好的配体效率与 sEH 催化三联体结合的新型支架。我们进一步确定了与 sEH 的子口袋（称为短分支和长分支）结合的片段命中。结构中保守的水分子在与长支链的结合中起着重要作用，而Asp496和Phe497的主链在短支链中通过片段命中形成氢键。片段命中及其晶体结构提供了配体与 sEH 结合的结构见解，这将有助于发现新型有效的 sEH 抑制剂。 (C) 2014 Elsevier Ltd. 保留所有权利。
Soluble epoxide hydrolase (sEH) is a component of the arachidonic acid cascade and is a candidate target for therapies for hypertension or inflammation. Although many sEH inhibitors are available, their scaffolds are not structurally diverse, and knowledge of their specific interactions with sEH is limited. To obtain detailed structural information about protein-ligand interactions, we conducted fragment screening of sEH, analyzed the fragments using high-throughput X-ray crystallography, and determined 126 fragment-bound structures at high resolution. Aminothiazole and benzimidazole derivatives were identified as novel scaffolds that bind to the catalytic triad of sEH with good ligand efficiency. We further identified fragment hits that bound to subpockets of sEH called the short and long branches. The water molecule conserved in the structure plays an important role in binding to the long branch, whereas Asp496 and the main chain of Phe497 form hydrogen bonds with fragment hits in the short branch. Fragment hits and their crystal structures provide structural insights into ligand binding to sEH that will facilitate the discovery of novel and potent inhibitors of sEH. (C) 2014 Elsevier Ltd. All rights reserved.