蛋白酪氨酸磷酸酯酶1B(PTP1B)是治疗2型糖尿病最有效的靶点之一，与PTP1B变构位点结合的活性成分比作用于催化活性位点的显示出更好的选择性和透膜性，但作用于变构位点的先导化合物极度缺乏。前期研究发现红大戟中的系列蒽醌具有PTP1B抑制作用，其中1个具有蒽醌并香豆素的新颖骨架，且抑制作用有较好的选择性，分子对接结果表明它可能是有效的PTP1B变构抑制剂。基于此，本项目拟应用现代色谱和波谱技术从已确定的活性部位分离和鉴定活性成分；并根据生源分析，以红大戟中含量较高的蒽醌为原料半合成新骨架化合物及其衍生物，对所得化合物应用酶抑制实验、分子对接和分子动力学模拟以及胰岛素抵抗C2C12骨骼肌细胞模型，系统性评价其PTP1B变构抑制活性，研究构效关系。研究工作可为研发选择性更好、具有新型作用机制的降血糖药物，提供新颖的活性模板结构或先导化合物。

Protein tyrosine phosphatase 1B (PTP1B) is currently verified to be one of the best validated biological target for non-insulin dependent diabetes. The compounds binding to the PTP1B allosteric site displayed better selectivity and cell-permeability than those binding to the catalytic active site, however, it is extremely lack of the active leading compounds targeted at the allosteric site. Our previous research found that a series of anthraquinones from Knoxia valerianoides displayed PTP1B inhibitory activity, one of them was an unprecedented hybrid anthraquinone-coumarin, displayed selective inhibitory effect against PTP1B over TCPTP, and further molecular docking indicated that it was a potent allosteric inhibitor. Based on the results obtained in the previous research, we plan to isolate and identify the active compounds by modern chromatographic and spectroscopic techniques from the targeted active factions, and semi-synthesize the compounds with novel structures and its derivatives using the main components isolated from Knoxia valerianoides as raw materials on the basis of the biogenetic analysis. The PTP1B allosteric inhibitory activity of all of the obtained compounds will be screened by enzyme inhibition assay, molecular docking and molecular dynamics simulations, as well as evaluated on the C2C12 muscle cell strains of insulin resistance model. Based on the above research, the structure-activity relationship will be analyzed. This research will provide novel active template structures or leading compound for the development of novel hypoglycemic drugs with better selectivity and new mechanism.