Citation: Lu Chenga, Liu Xiang, Tang Yanting, Xu Yongxue, Zhong Weilong, Sun Taoa, Zhou Honggang. Design, Synthesis of a Novel Phosphatase 1B Inhibitor and the Evaluation of Its Biology Activity and Toxicity in vitro[J]. Acta Chimica Sinica, ;2015, 74(2): 155-164. doi: 10.6023/A15090597 shu

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

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

Corresponding author: Zhou Honggang, honggang.zhou@nankai.edu.cn
Received Date: 11 September 2015

Fund Project: the National Natural Science Foundation of China No. 81102374the National Biomedical Special Project of International Innovation Park Nos. 11ZCKFSY06900, 10ZCKFSY08600, 14ZCZDSY00038

Figures(11)

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.
- protein tyrosine phosphatase (PTPase) 1B,
- crystal diffraction,
- structure-based drug design,
- synthesis,
- activity
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沈阳化工大学材料科学与工程学院沈阳 110142