Isothiazolidinone heterocycles as inhibitors of protein tyrosine phosphatases: Synthesis and structure-activity relationships of a peptide scaffold
Isothiazolidinone heterocycles as inhibitors of protein tyrosine phosphatases: Synthesis and structure-activity relationships of a peptide scaffold
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DOI：
10.1016/j.bmc.2006.05.032
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发表时间：
2006-09-01
影响因子：
3.5
通讯作者：
Combs, Andrew P.
中科院分区：
文献类型：
--
作者：
Yue, Eddy W.;Wayland, Brian;Combs, Andrew P.
基于结构的设计和发现异噻唑烷酮 (IZD) 杂环作为磷酸酪氨酸 (pTyr) 的模拟物，导致鉴定出新型含 IZD 的蛋白酪氨酸磷酸酶 1B (PTP1B) 抑制剂。描述了含有 IZD 的 PTP1B 肽抑制剂的结构-活性关系 (SAR)，以及通过 Suzuki 偶联合成芳基-IZD 片段的新方法。 SAR 显示，与不饱和 IZD (25)、噻二唑烷酮 (TDZ) (38) 和区域异构不饱和 IZD (31) 相比，饱和 IZD 杂环 (42) 是最有效的杂环 pTyr 模拟物。解析了与 PTP1B 复合的 11c 和 25 的 X 射线晶体结构，并揭示了活性位点几乎相同的结合相互作用。从头计算有效地解释了 (S)-IZD 的强结合，这是由于 IZD 在其低能构象中的预组织结合。 (c) 2006 Elsevier Ltd. 保留所有权利。
The structure-based design and discovery of the isothiazolidinone (IZD) heterocycle as a mimic of phosphotyrosine (pTyr) has led to the identification of novel IZD-containing inhibitors of protein tyrosine phosphatase 1B (PTP1B). The structure-activity relationships (SARs) of peptidic IZD-containing inhibitors of PTP1B are described along with a novel synthesis of the aryl-IZD fragments via a Suzuki coupling. The SAR revealed the saturated IZD heterocycle (42) is the most potent heterocyclic pTyr mimetic compared to the unsaturated IZD (25), the thiadiazolidinone (TDZ) (38), and the regioisomeric unsaturated IZD (31). The X-ray crystal structures of 11c and 25 complexed with PTP1B were solved and revealed nearly identical binding interactions in the active site. Ab initio calculations effectively explain the strong binding of the (S)-IZD due to the preorganized binding of the IZD in its low energy conformation. (c) 2006 Elsevier Ltd. All rights reserved.