Key Laboratory of Experimental Marine Biology, Institute of Oceanology, Chinese Academy of Sciences, Qingdao, China; Laboratory for Marine Drugs and Bioproducts, Qingdao National Laboratory for Marine Science and Technology, Qingdao, China.
Key Laboratory of Marine Drugs, The Ministry of Education of China, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, China.
Eur J Med Chem. 2017 Jul 7;134:24-33. doi: 10.1016/j.ejmech.2017.04.004. Epub 2017 Apr 4.
Protein tyrosine phosphatase 1B (PTP1B) is a key negative regulator of insulin signaling pathway. Inhibition of PTP1B is expected to improve insulin action. Appropriate selectivity and permeability are the gold standard for excellent PTP1B inhibitors. In this work, molecular hybridization-based screening identified a selective competitive PTP1B inhibitor. Compound 10a has IC values of 199 nM against PTP1B, and shows 32-fold selectivity for PTP1B over the closely related phosphatase TCPTP. Molecule docking and molecular dynamics studies reveal the reason of selectivity for PTP1B over TCPTP. Moreover, the cell permeability and cellular activity of compound 10a are demonstrated respectively.
蛋白酪氨酸磷酸酶 1B（PTP1B）是胰岛素信号通路的关键负调控因子。抑制 PTP1B 有望改善胰岛素的作用。适当的选择性和通透性是优秀 PTP1B 抑制剂的金标准。在这项工作中，基于分子杂交的筛选鉴定出一种选择性竞争的 PTP1B 抑制剂。化合物 10a 对 PTP1B 的 IC 值为 199 nM，对密切相关的磷酸酶 TCPTP 的选择性为 32 倍。分子对接和分子动力学研究揭示了 PTP1B 相对于 TCPTP 选择性的原因。此外，还分别证明了化合物 10a 的细胞通透性和细胞活性。
