基于昆虫N-乙酰己糖胺酶结构的抑制剂设计
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- 英文论文题名：Structure-based inhibitor design of insect β-acetylglucosaminidase
- 论文作者：刘田 ; 郭朋 ; 钱旭红 ; 杨青
- 英文论文作者：Tian Liu ; Peng Guo ; Xuhong Qian ; Qing Yang ; School of Life Science and Biotechnology ; Dalian University of Technology ; School of Pharmacy ; East China University of Science and Technology
- 年：2016
- 作者机构：大连理工大学生命科学与技术学院;华东理工大学药学院;
- 论文关键词：昆虫 ; 蜕皮 ; 几丁质 ; N-乙酰己糖胺酶 ; 抑制剂
- 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：TQ450.1
- 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：261k
- 原文格式：D
- 会议级别：全国
摘要
昆虫表皮是由几丁质及蛋白质等组成的复杂且高度有序的结构。由于昆虫必须周期性蜕皮以满足其生长发育的需要,使得其负责其蜕皮过程的关键酶成为有潜力的绿色农药靶标。蛋白质组研究表明,N-乙酰己糖胺酶Hex1是昆虫蜕皮液中几丁质水解酶"211"组合中的一员,RNA干扰该酶会导致昆虫蜕皮异常而死亡。我们解析了亚洲玉米螟N-乙酰己糖胺酶OfHex1的晶体结构,并且发现其活性口袋入口处特殊的Loop结构及关键氨基酸残基Val327、Glu368及Trp490决定了其生理功能特异性,同时也是基于结构选择性抑制剂设计的重要靶点~([1])。基于以上发现,我们通过对天然产物TMG-chitotriomycin及催化反应中间体类似物NAG-thiazoline的结构改造,获得了高活性及高选择性的OfHex1抑制剂TMG-(GlcNAc)_2及NMAGT,其中前者的K_i值为70 nM~([2])。接下来,我们对选择性抑制人类N-乙酰己糖胺酶HsHex的抑制剂M-31850,通过理性设计实现了选择性逆转,获得的选择性抑制OfH ex1的萘酰亚胺衍生物Q2~([3])。本研究为基于靶标结构的抑制剂设计提供了思路,也为针对昆虫蜕皮过程的绿色农药开发提供了先导化合物。
NAG-thiazoline(NGT) and its derivatives are well-known inhibitors against most β-acetylglucosaminidases(β-GlcNAcases) except for insect and bacterial chitinolytic β-GlcNAcases,e.g.,the molting-indispensable OfHex1 from the insect Ostrinia furnacalis.Here,we report the co-crystal structure of OfHex1-NGT,revealing a rather large active pocket in OfHex1 that may account for the poor inhibitory activity of NGT.Therefore,a bulky substituent on the thiazoline ring of NGT was designed and synthesized.The resulting compound(NMAGT) was determined to be a submicromolar inhibitor of OfHex1 with a K_i value of 0.13 μM,which is 600-fold lower than K_i value of NGT.Molecular dynamics simulation analysis supported the good fit of NMAGT to the active pocket.
NAG-thiazoline(NGT) and its derivatives are well-known inhibitors against most β-acetylglucosaminidases(β-GlcNAcases) except for insect and bacterial chitinolytic β-GlcNAcases,e.g.,the molting-indispensable OfHex1 from the insect Ostrinia furnacalis.Here,we report the co-crystal structure of OfHex1-NGT,revealing a rather large active pocket in OfHex1 that may account for the poor inhibitory activity of NGT.Therefore,a bulky substituent on the thiazoline ring of NGT was designed and synthesized.The resulting compound(NMAGT) was determined to be a submicromolar inhibitor of OfHex1 with a K_i value of 0.13 μM,which is 600-fold lower than K_i value of NGT.Molecular dynamics simulation analysis supported the good fit of NMAGT to the active pocket.
引文
[1]Liu,T.,Zhang,H.,Liu,F.,et al.,J.Biol.Chem.2011,286,4049-4058.
[2]Liu,T.,Xia,M.,Zhang,H.,et al.,FEBS lett.2015,589,110-116.
[3]Liu,T.,Guo,P.,Zhou,Y.,et al.,Sci.Rep.2014,4,6188.
[2]Liu,T.,Xia,M.,Zhang,H.,et al.,FEBS lett.2015,589,110-116.
[3]Liu,T.,Guo,P.,Zhou,Y.,et al.,Sci.Rep.2014,4,6188.