Inhibition of striatal-enriched protein tyrosine phosphatase by targeting computationally revealed cryptic pockets
Inhibition of striatal-enriched protein tyrosine phosphatase by targeting computationally revealed cryptic pockets
复制标题
通过靶向计算揭示的隐秘口袋来抑制富含纹状体的蛋白酪氨酸磷酸酶
DOI：
10.1016/j.ejmech.2020.112131
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发表时间：
2020-03-15
影响因子：
6.7
通讯作者：
Fang, Hao
中科院分区：
文献类型：
--
作者：
Hou, Xuben;Sun, Jin-peng;Fang, Hao
隐秘口袋在晶体结构中不明显，为药物开发的传统结合位点提供了有前景的替代选择。然而，识别隐秘口袋极具挑战性，且隐秘口袋的治疗潜力仍不明确。在此，我们报道了基于隐秘口袋检测发现的纹状体富集蛋白酪氨酸磷酸酶（STEP）的新型抑制剂，STEP是多种神经精神疾病的潜在药物靶点。通过结合分子动力学模拟和以片段为中心的拓扑映射的使用，我们识别出了瞬时开放的隐秘口袋，并通过基于结构的虚拟筛选确定了12种新的STEP抑制支架。定点突变验证了ST3与预测的隐秘口袋的结合。此外，最有效和选择性最强的抑制剂能够调节PC12细胞中ERK1/2和Pyk2的磷酸化。（C）2020爱思唯尔马松公司。版权所有。
Cryptic pockets, which are not apparent in crystallographic structures, provide promising alternatives to traditional binding sites for drug development. However, identifying cryptic pockets is extremely challenging and the therapeutic potential of cryptic pockets remains unclear. Here, we reported the discovery of novel inhibitors for striatal-enriched protein tyrosine phosphatase (STEP), a potential drug target for multiple neuropsychiatric disorders, based on cryptic pocket detection. By combining the use of molecular dynamics simulations and fragment-centric topographical mapping, we identified transiently open cryptic pockets and identified 12 new STEP inhibition scaffolds through structure-based virtual screening. Site-directed mutagenesis verified the binding of ST3 with the predicted cryptic pockets. Moreover, the most potent and selective inhibitors could modulate the phosphorylation of both ERK1/2 and Pyk2 in PC12 cells. (C) 2020 Elsevier Masson SAS. All rights reserved.