理论模拟与创新药物发现及蛋白质动态调控研究
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- 英文论文题名：Theoretical-simulation-driven innovate drug discovery and protein dynamic regulation research
- 论文作者：张豪 ; 蒋华良 ; 罗成
- 英文论文作者：Hao Zhang ; H.Jiang ; C.Luo ; State Key Laboratory of Drug Research ; Shanghai Institute of Materia Medica ; Chinese Academy of Sciences
- 年：2016
- 作者机构：中国科学院上海药物研究所;
- 论文关键词：药物设计 ; 先导化合物发现 ; 表观遗传学 ; 蛋白-蛋白相互作用
- 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：TQ460.1
- 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：114k
- 原文格式：D
- 会议级别：全国
摘要
创新药物的研发依赖于全新的药物靶标和药物先导化合物的发现,而传统实验技术难以满足创新药物发现过程中靶标发现、先导化合物设计研究需求。我们综合运用计算生物学与实验生物学方法,针对多个疾病体系开展药物靶标、先导化合物发现与设计及蛋白质动态调控机制的研究,发现了一批靶向全新位点的活性化合物,如第一个靶向铜离子伴侣蛋白Atoxl和CCS的小分子抑制剂;第一个靶向EZH2-EED蛋白质相互作用界面的小分子抑制剂;第一个RNA去甲基化酶FTO的小分子抑制剂等。同时,我们采用分子动力学模拟与实验验证相结合的手段,研究了多种重要蛋白质动态调控机制,首次阐明了DNA主动去甲基化酶TET的底物选择性机制;首次解释了eIF4A调控ATP水解与RNA解旋的机制;首次明确了Oct4识别DNA的分子机制、发现可促进体细胞重编程的功能突变体等。这些理论模拟驱动实验研究的成功案例,为创新药物研发提供了极具潜力的新靶标和先导化合物,也进一步体现了多学科交叉在创新药物和机理研究中的重要性。
Through a theoretical-simulation-driven strategy,we combined computational biology and experimental biology to conduct target identification,lead discovery and design and protein dynamic research towards several important disease systems.In the aspect of lead discovery,we have reported the first inhibitor that targets copper chaperone Atoxl and CCS;the first small molecule inhibitor that binds to the EZH2-EED protein interaction interface;the first small molecule inhibitor for RNA demethylase FTO and etc.Meanwhile,through a comprehensive application of molecular dynamics simulation and biochemical assays,for the first time,we revealed the mechanism of substrate preference for DNA demethylase TET;the regulatory mechanism of eIF4A in ATP hydrolysis and RNA unwinding;the DNA recognition mechanism of Oct4 and etc.These successful cases in theoretical-simulation-driven experimental studies provide promising new targets and lead compounds for innovate drug discovery and also reveal important roles of interdisciplinary research in innovate drug discovery.
Through a theoretical-simulation-driven strategy,we combined computational biology and experimental biology to conduct target identification,lead discovery and design and protein dynamic research towards several important disease systems.In the aspect of lead discovery,we have reported the first inhibitor that targets copper chaperone Atoxl and CCS;the first small molecule inhibitor that binds to the EZH2-EED protein interaction interface;the first small molecule inhibitor for RNA demethylase FTO and etc.Meanwhile,through a comprehensive application of molecular dynamics simulation and biochemical assays,for the first time,we revealed the mechanism of substrate preference for DNA demethylase TET;the regulatory mechanism of eIF4A in ATP hydrolysis and RNA unwinding;the DNA recognition mechanism of Oct4 and etc.These successful cases in theoretical-simulation-driven experimental studies provide promising new targets and lead compounds for innovate drug discovery and also reveal important roles of interdisciplinary research in innovate drug discovery.
引文
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2.Wang J.;Luo C.;Shan C.;You Q.Nature Chem,2015,7:968.
3.Lu J.;Jiang C.;Li X.;Jiang L.Nucleic Acids Res,2015,43(21):10157.
4.Kong X.;Liu J.;Li L.;Yue L.Nucleic Acids Res,2015,43(9):4381.
5.Huang Y.;Yan J.;Li Q.;Li J.Nucleic Acids Res,2015,43(1):373.
6.Zhang J.;Liu H.;Zhu K.;Gong S.PNAS,2014,111(37):13517.
7.Kong X.;Chen L.;Jiao J.;Jiang X.J Med Chem,2014,57(22):9512.