Acta Chim. Sinica ›› 2016, Vol. 74 ›› Issue (2): 155-164.DOI: 10.6023/A15090597 Previous Articles     Next Articles



卢骋a, 刘祥b, 唐延婷b, 徐永学b, 仲威龙a, 孙涛a, 周红刚a   

  1. a 药物化学生物学国家重点实验室 南开大学药学院和天津市分子药物研究重点实验室 天津 300071;
    b 天津国际生物医药联合研究院高通量药物筛选中心 天津 300457
  • 收稿日期:2015-09-11 出版日期:2016-02-15 发布日期:2015-12-23
  • 通讯作者: 周红刚
  • 基金资助:


Design, Synthesis of a Novel Phosphatase 1B Inhibitor and the Evaluation of Its Biology Activity and Toxicity in vitro

Lu Chengaa, Liu Xiangb, Tang Yantingb, Xu Yongxueb, Zhong Weilonga, Sun Taoaa, Zhou Hongganga   

  1. a State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin 300071;
    b High Throughput Molecular Drug Discovery Center, Tianjin International Joint Academy of Biotechnology and Medicine, Tianjin 300457
  • Received:2015-09-11 Online:2016-02-15 Published:2015-12-23
  • Supported by:

    Project supported by the National Natural Science Foundation of China (No. 81102374) and the National Biomedical Special Project of International Innovation Park (Nos. 11ZCKFSY06900, 10ZCKFSY08600, 14ZCZDSY00038).

Protein tyrosine phosphatase 1B (PTP1B) is an enzyme that downregulates the insulin receptor. It has been considered as one of the drug targets of diabetes, and the inhibitors for PTP1B to treat type II diabetes have received considerable attention. The study reports a discovery of a new lead compound inhibiting PTP1B. In this work, PTP1B protein was expressed, purified and crystallized to the resolution of 2.1 Angstrom in the condition of 19%~21% PEG8000, 200 mmol/L Mg(Ac)2·4H2O. Structural based fragment screening was then performed against 768 fragment chemical compounds. These small molecular fragments were soaked with the PTP1B crystals, and three of them were found to bind at the active site A of PTP1B in the crystals. Then 14 kinds of published molecules which bind to the second active site (site B) were chosen. With the structures of these bound fragment compounds, hundreds of moleculars were calculated by computer aided drug design. Compound 20 was selected as the target compound, and it was synthesized by 13 steps with the total yield of 1.7%. The structure of compound 20 was characterized by 1H NMR and HRMS data. Bioassay of inhibition of PTP1B by the new compounds revealed its IC50 at (3.4±1.2) μmol/L, which was better than that of the positive control drug-sodium vanadate. The result of measurement of glucose uptake by insulin resistant HepG2 cells showed that the new compound can improve glucose uptake and had similar effect as Pioglitazone. The acute toxicity of the new compound was tested by using zebrafish larvae at two different concentrations (50 and 500 μmol/L). The results showed there was no significant difference in heart rate, blood flow and morphology between the experiment and control group of zebrafish. All the results above implied the new compound has a good inhibition on PTP1B and low acute toxicity. It may be a potential lead compound for further drug discovery.

Key words: protein tyrosine phosphatase (PTPase) 1B, crystal diffraction, structure-based drug design, synthesis, activity