Protein tyrosine phosphatase 1B (PTP1B) is a member of the phosphotyrosine phosphatase family and plays an important role in the signal transduction of diabetes. Inhibition of PTP1B activity can increase insulin sensitivity and reduce blood sugar levels. Therefore, it is urgent to find compounds with novel structures that can inhibit PTP1B. This study designed imidazolidine-2,4-dione derivatives through the computer-aided drug design (CADD) strategy, and the Comp#10 showed outstanding inhibitory ability. (IC₅₀ = 2.07 μM) and selectivity. The inhibitory mechanism at molecular level of Comp#10 on PTP1B was studied by molecular dynamics simulation. The results show that the catalytic region of PTP1B protein is more stable, which makes the catalytic sites unsuitable for exposure. Interestingly, the most obvious changes in the interaction between residues in the P-loop region (such as: His214, Cys215, and Ser216). In short, this study reported for the first time that imidazolidine-2,4-dione derivatives as novel PTP1B inhibitors had good inhibitory activity and selectivity, providing new ideas for the development of small molecule PTP1B inhibitors.

蛋白酪氨酸磷酸酶 1B (PTP1B) 是磷酸酪氨酸磷酸酶家族的一员，在糖尿病的信号转导中起重要作用。抑制 PTP1B 活性可以增加胰岛素敏感性并降低血糖水平。因此，迫切需要寻找能够抑制PTP1B的具有新结构的化合物。本研究通过计算机辅助药物设计 (CADD) 策略设计了咪唑烷-2,4-二酮衍生物，Comp#10 显示出出色的抑制能力。(IC ₅₀ = 2.07 μM) 和选择性。通过分子动力学模拟研究了Comp#10在分子水平上对PTP1B的抑制机制。结果表明，PTP1B蛋白的催化区域更稳定，使得催化位点不适合暴露。有趣的是，最明显的变化是 P-loop 区域中残基之间的相互作用（如：His214、Cy​​s215 和 Ser216）。总之，本研究首次报道咪唑烷-2,4-二酮衍生物作为新型PTP1B抑制剂具有良好的抑制活性和选择性，为小分子PTP1B抑制剂的开发提供了新思路。