PTP-Shp2抑制剂flavoglaucin的发现与研究  

Discovery of flavoglaucin as an inhibitor of PTP-Shp2

作　　者：张雪莲[1] 郑海洲[1] 徐岩[1] 路新华[1] 朱京童[1] 郑智慧[1] Zhang Xue-lian;Zheng Hai-zhou;Xu Yan;Lu Xin-hua;Zhu Jing-tong;Zheng Zhi-hui(New Drug Research ＆ Development Limited Company of North China Pharmaceutical Group Corporation, National Microbial Medicine Engineering ＆ Research Center, Industry Microorganism Metabolites Engineering Technology of Hebei ＆ Research Center, Shijiazhuang Engineering Laboratory for New Drugs Screening, Shijiazhuang 050015)

机构地区：[1]华北制药集团新药研究开发有限责任公司微生物药物国家工程研究中心河北省工业微生物代谢工程技术研究中心石家庄市新药筛选技术工程实验室,石家庄050015

出　　处：《中国抗生素杂志》2018年第6期683-687,共5页Chinese Journal of Antibiotics

基　　金：微生物来源药物发酵及分离纯化中试条件建设及质量管理体系建设(No.169676404G)

摘　　要：目的以蛋白酪氨酸磷酸酶Shp2(PTP-Shp2)为靶点发现其小分子抑制剂。方法高通量筛选小分子PTP-Shp2抑制剂并进行动力学分析,利用计算机分子对接分析抑制剂在PTP-Shp2上的结合位点。结果从本实验室微生物代谢产物化合物库中发现了PTP-Shp2蛋白抑制剂flavoglaucin,其IC_(50)值为5.08μmol/L。米氏方程的双倒数分析证明flavoglaucin是非竞争的PTP-Shp2蛋白抑制剂。计算机分子对接结果显示flavoglaucin结合在PTP-Shp2蛋白的WDP loop上并形成3个氢键。结论 Flavoglaucin是微生物来源的新型小分子PTP-Shp2抑制剂。Objective To discover small molecule inhibitors of protein tyrosine phosphatase Shp2 （PTP-Shp2）. Methods We used a high-throughput screening method to find small molecular inhibitors of PTP-Shp2 and kinetic analysis of Shp2 inhibition was implemented. We assessed the inhibitor binding sites in Shp2 using molecular docking. Results In this study, flavoglaucin was identified as a Shp2 inhibitor from products of microbial metabolism in our lab by a high-throughput screening method with an IC50 value of 5.08μmol/L. The lineweaver-burk analysis suggested that flavoglaucin was a non-competitive inhibitor of Shp2. Molecular docking of flavoglaucin with Shp2 showed that flavoglaucin formed three hydrogen bonds with the WDP loop of Shp2. Conclusion Flavoglaucin which is from products of microbial metabolism is a novel inhibitor of Shp2.

关 键 词：蛋白酪氨酸磷酸酶Shp2 抑制剂 Flavoglaucin 

分 类 号：Q933[生物学—微生物学]