蛋白酪氨酸磷酸酶1B（PTP1B）已被证明是治疗癌症、糖尿病和其他疾病的一个有吸引力的靶点。尽管已经开发了许多具有不同框架的PTP1B抑制剂，但仍然缺乏具有高特异性和可接受的药理特性的PTP1B抑制剂。因此，迫切需要开发更多的方法来研究PTP1B的复杂作用机制和设计理想的PTP1B调节剂的配体。在这项工作中，我们开发了一种潜在的分子动力学（MD）分析模式，从不同的角度分析了化合物6a和6e对PTP1B的作用机制，包括配体和蛋白质的稳定能力、相互作用和结合位点、结合能、残基之间的相对运动以及蛋白质内部相互作用的变化。模拟结果表明，由于其较小的分子体积（326 Å3）、匹配的电负性和增强了残基的正相关运动，化合物6a与PTP1B的活性口袋结合更为稳定，尤其是WPD环和P环。最后，通过酶动力学测定验证了化合物6a作为PTP1B的竞争性抑制剂。这项工作成功地从多个方面研究了化合物6a对PTP1B的作用机制，丰富了PTP1B与抑制剂之间相互作用模式的分析。总之，我们希望这项工作能为未来设计和开发更多的新型理想PTP1B抑制剂提供更多理论信息。版权所有 © 2023 Elsevier Inc. 发布。

Protein tyrosine phosphatase 1B (PTP1B) has proven to be an attractive target for the treatment of cancer, diabetes and other diseases. Although many PTP1B inhibitors with various scaffolds have been developed, there is still a lack of PTP1B inhibitor with high specificity and acceptable pharmacological properties. Therefore, it is urgent to develop more methods to explore complex action mode of PTP1B and ligands for designing ideal PTP1B modulators. In this work, we developed a potential molecular dynamics (MD) analytic mode to analyze the mechanism of active compounds 6a and 6e against PTP1B from different perspectives, including the stable ability, interactions and binding site of ligand and protein, the binding energy, relative movement between residues and changes in protein internal interactions. The simulated results demonstrated that compound 6a bound more stably to the active pocket of PTP1B than 6e due to its smaller molecular volume (326 Å3), matched electronegativity, and enhanced the positive correlation motion of residues, especially for WPD loop and P loop. Lastly, compound 6a as a competitive inhibitor for PTP1B was verified by enzyme kinetic assay. This work successfully studied the mechanism of compound 6a against PTP1B from various aspects, enriched the analysis of interaction mode between PTP1B and inhibitors. In summary, we hope that this work could provide more theoretical information for designing and developing more novel and ideal PTP1B inhibitors in the future.Copyright © 2023. Published by Elsevier Inc.