| 引用本文: | 黄朝辉,胡海荣,雷贾毅,楚勇,叶德泳.新型苯并硫氮杂酮类非ATP竞争GSK-3β抑制剂的设计、合成和活性评价[J].中国现代应用药学,2012,29(11):988-992. |
| HUANG Zhaohui,HU Hairong,LEI Jiayi,CHU Yong,YE Deyong.Design, Synthesis and in Vitro Test of Novel Non-ATP Competitive Glycogen Synthase Kinase-3β(GSK-3β) Inhibitors[J].Chin J Mod Appl Pharm(中国现代应用药学),2012,29(11):988-992. |
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| 摘要: |
| 目的 寻找新型的非ATP竞争糖原合成酶激酶-3β(GSK-3β)抑制剂。方法 针对GSK-3β的非ATP结合的底物作用位点为靶点，采用Autodock程序对类药性小分子库Maybridge进行虚拟筛选寻找新型GSK-3β抑制剂。采用克脑文格尔反应，环合及N-烷基化反应制备目标化合物。采用体外酶抑制活性测试目标化合物的活性。结果 化合物2-(2-呋喃基)-5-苄基-2,3-二氢苯并[b][1,4]硫氮杂-4(5H)-酮对GSK-3β具有中等抑制活性(IC50 47.69±2.38 μmol·L-1)。结论 活性化合物的结构与目前报道的其他GSK-3β抑制剂不同，可望作为新的先导化合物，值得进一步研究。 |
| 关键词: 糖原合成酶激酶-3β 虚拟筛选 抑制剂 合成 |
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| Design, Synthesis and in Vitro Test of Novel Non-ATP Competitive Glycogen Synthase Kinase-3β(GSK-3β) Inhibitors |
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HUANG Zhaohui1, HU Hairong2, LEI Jiayi3, CHU Yong3, YE Deyong3
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1.Ningbo Institute for Drug Control, Ningbo 315048, China;2.School of Life Sciences, Fudan University, Shanghai 200433, China;3.School of Pharmacy, Fudan University, Shanghai 200032, China
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| Abstract: |
| OBJECTIVE To discover novel non-ATP competitive glycogen synthase kinase-3β(GSK-3β) inhibitors. METHODS A virtual screening was conducted by Autodock program, which docked the small drug-like molecules of Maybridge library at the non-ATP binding site of GSK-3β. The target compounds had been designed based on the virtual screening result and successfully synthesized through Knoevenagel reaction, cyclization and N-alkylation. The inhibition to GSK-3β was tested by in vitro enzamic test. RESULTS 5-benzyl-2-(furan-2-yl)-2,3-dihydrobenzo[b][1,4] thiazepin-4(5H)-one showed moderate inhibition to GSK-3β in vitro (IC50 47.69±2.38 μmol·L-1). CONCLUSION The discovered new active compound is structurally different to other inhibitors of GSK-3β and worthy of further study as a novel lead compound. |
| Key words: glycogen synthase kinase-3β(GSK-3β) virtual screening inhibitor synthesis |
