天然黄酮类MAGL抑制剂的发现
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- 英文论文题名：Discovery of natural flavonoid MAGL inhibitors
- 论文作者：马佳慧 ; 杨若林 ; 刘坚华
- 英文论文作者：Ma Jiahui ; Yang Ruolin ; Liu Jianhua ; Department of Chemistry ; Shanghai Jiao Tong University School of Medicine
- 年：2016
- 作者机构：上海交通大学医学院化学教研室;
- 论文关键词：MAGL抑制剂 ; 计算机辅助虚拟筛选 ; 先导化合物
- 英文论文关键词：MAGL inhibitors ; virtual high throughput screening ; lead compounds
- 会议召开时间：2016-07-01
- 会议录名称：中国化学会第30届学术年会摘要集-第二十八分会：化学生物学
- 语种：中文
- 分类号：TQ464
- 学会代码：ZGHY
- 会议名称：中国化学会第30届学术年会-第二十八分会 ; 化学生物学
- 会议地点：中国辽宁大连
- 主办单位：中国化学会
- 学会名称：中国化学会
- 页数：1
- 文件大小：375k
- 原文格式：D
- 会议级别：全国
摘要
单酸甘油酯酶(MAGL)是内源性大麻素系统的一个重要组成部分,主要代谢内源性大麻素2-花生四烯酸甘油酯(2-AG)~([1])。MAGL是一个与疼痛~([2])、阿兹海默症(AD)~([3])和肿瘤~([4])等疾病相关的新靶点,因此研发MAGL抑制剂将为相关疾病的治疗带来新的契机。本实验室前期通过计算机辅助虚拟筛选~([5])结合活性测试方法,在发现丹参酮IIA[6]具有抑制MAGL活性的同时,发现异黄酮类化合物葛根素也具有微弱的MAGL抑制活性。在此基础上,一系列与葛根素结构类似的黄酮、异黄酮和二氢异黄酮类化合物(带有糖苷的化合物和不带糖苷的衍生物)被用于MAGL抑制活性的研究。测试结果显示不带糖苷的黄酮类化合物展现出更高的MAGL抑制活性。其中活性最好的化合物抑制MAGL的IC50达到36μM。
Monoacylglycerol lipase(MAGL) is the primary enzyme that metabolizes the endocannabinoid 2-arachidonoylglycerol in the brain.It is a novel target related to a variety of diseases,including pain,Alzheimer's disease,tumor,and etc.Discovery and development of MAGL inhibitors will bring new hope for treatment of related diseases.By using computer aided virtual screening and biological assessment,our laboratory has successfully identified tanshinone IIA as a natural MAGL inhibitor in a concentration dependent manner with an IC_(50) value of 48 μM.Meanwhile,isoflavones puerarin also showed a weak inhibition.On the basis of this finding,a series of flavones,isoflavones and dihydroisoflavones(with or without the glycosides parts) which shared similar structure to puerarin were selected to study the inhibitory activity against MAGL.The biological assessment showed that flavonoids without the glycosides had better activities,and the best compound tested presented the highest activity with an IC_(50) value of 36μM.
Monoacylglycerol lipase(MAGL) is the primary enzyme that metabolizes the endocannabinoid 2-arachidonoylglycerol in the brain.It is a novel target related to a variety of diseases,including pain,Alzheimer's disease,tumor,and etc.Discovery and development of MAGL inhibitors will bring new hope for treatment of related diseases.By using computer aided virtual screening and biological assessment,our laboratory has successfully identified tanshinone IIA as a natural MAGL inhibitor in a concentration dependent manner with an IC_(50) value of 48 μM.Meanwhile,isoflavones puerarin also showed a weak inhibition.On the basis of this finding,a series of flavones,isoflavones and dihydroisoflavones(with or without the glycosides parts) which shared similar structure to puerarin were selected to study the inhibitory activity against MAGL.The biological assessment showed that flavonoids without the glycosides had better activities,and the best compound tested presented the highest activity with an IC_(50) value of 36μM.
引文
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2.Hohmann,A.G.,Br J Pharmacol 2007,150(6),673-675.
3.Chen,R.;Zhang,J.;Wu,Y.;et al.Cell Rep 2012,2(5),1329-1339.
4.Ye,L.;Zhang,B.;Seviour,E.G.;et al.Cancer Lett 2011,307(1),6-17.
5.Zoete,V.;Grosdidier,A.;Michielin,O.,Cell Mol Med 2009,13(2),238-248.
6.Yang,R.;Lu,Y.;Liu,J.,Med.Chem.Commun.2014,5(10),1528-1532.