Fast Identification of Novel Lymphoid Tyrosine Phosphatase Inhibitors Using Target-Ligand Interaction-Based Virtual Screening
Fast Identification of Novel Lymphoid Tyrosine Phosphatase Inhibitors Using Target-Ligand Interaction-Based Virtual Screening
复制标题
使用基于靶配体相互作用的虚拟筛选快速鉴定新型淋巴酪氨酸磷酸酶抑制剂
DOI：
10.1021/jm500692u
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发表时间：
2014-11-27
影响因子：
7.3
通讯作者：
Fang, Hao
中科院分区：
文献类型：
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作者：
Hou, Xuben;Li, Rong;Fang, Hao
淋巴组织特异性酪氨酸磷酸酶(LYP)是免疫细胞的重要信号调节因子，与多种自身免疫性疾病有关，包括1型糖尿病、类风湿性关节炎和系统性红斑狼疮。最近的研究表明，LYP是治疗自身免疫性疾病的潜在药物靶点。在此，我们应用了一种基于靶标配体相互作用的虚拟筛选方法来寻找新的LYP抑制剂。从8个可逆抑制剂(K-I值在2.87~28.03µM)和1个共价抑制剂(K-I=40.98+/-13.19µM)中鉴定了9个具有新型支架的LYP抑制剂。在初步实验中，前四个化合物(A2、A15、A19和A26)表现出对其他磷酸酶的选择性，动力学分析表明这些化合物是LYP的竞争性抑制剂。化合物A15和A19通过抑制T细胞中LYP的活性，上调TCR(T细胞受体)介导的信号和转录激活。通过基于靶标配体相互作用的虚拟筛选发现的新的LYP选择性抑制剂的化学类型可能为LYP靶向治疗的开发提供新的线索。
Lymphoid-specific tyrosine phosphatase (Lyp), a critical signaling regulator of immune cells, is associated with various autoimmune diseases, including type 1 diabetes, rheumatoid arthritis, and systemic lupus erythematosus. Recent research suggests that Lyp is a potential drug target for autoimmune diseases. Herein, we applied a targetligand interaction-based virtual screening method to identify novel Lyp inhibitors. Nine Lyp inhibitors with novel scaffolds were identified with eight reversible inhibitors (K-i values ranged from 2.87 to 28.03 mu M) and one covalent inhibitor (K-i = 40.98 +/- 13.19 mu M). The top four compounds (A2, A15, A19, and A26) displayed selectivity over other phosphatases in preliminary experiments, and kinetic analysis indicated that these compounds are competitive inhibitors of Lyp. Compounds A15 and A19 up-regulated TCR (T cell receptor) mediated signaling and transcriptional activation through inhibition of Lyp activity in T cells. The new chemotypes of Lyp selective inhibitors identified through the targetligand interaction-based virtual screening may provide new leads for Lyp targeted therapeutic development.