针对SAM依赖的甲基转移酶靶标特异性打分函数的发展及应用——DOT1L抑制剂筛选
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- 英文论文题名：Virtual Screening to Identify Novel DOT1L Inhibitors by a Target Scoring Function for SAM-dependent methyltransferase family
- 论文作者：王玉兰 ; 李林娟 ; 罗成 ; 郑明月 ; 蒋华良
- 英文论文作者：Yulan Wang ; Linjuan Li ; Cheng Luo ; Mingyue Zheng ; Hualiang Jiang ; Shanghai Institute of Materia Medica ; Chinese Academy of Sciences ; University of Chinese Academy of Sciences ; School of Life Science and Technology ; Shanghai Tech University
- 年：2016
- 作者机构：中国科学院上海药物研究所药物发现与设计中心;中国科学院大学;上海科技大学生命科学与技术学院;
- 论文关键词：甲基转移酶 ; DOT1L ; 靶标特异性打分函数 ; 虚拟筛选 ; 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-第二十五分会：化学信息学与化学计量学
- 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-第二十五分会 ; 化学信息学与化学计量学
- 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：117k
- 原文格式：D
- 会议级别：全国
摘要
表观遗传修饰相关的甲基转移酶在基因转录调控中发挥着重要作用,与肿瘤的发生、发展和预后密切相关,已成为抗肿瘤药物研究的重要靶点。DOT1L是一种组蛋白甲基转移酶,主要甲基化组蛋白3上的第79位赖氨酸,在MLL-重组相关白血病发生发展过程中扮演着重要的角色。本研究中,我们发展了一种甲基转移酶靶标特异性的打分函数SAM-score,并将该打分函数应用于DOT1L抑制剂筛选发现了DOT1L小分子抑制剂DCD-17。DCD-17是一类具有非核苷类骨架,对DOT1L较高抑制活性(IC50=4.5uM)和选择性的小分子抑制剂。在细胞试验中,DCD-17表现出显著的MLL-重组细胞增殖抑制活性(ED50=21.8uM)。此外,我们用分子对接模拟DCD-17及其类似物与DOT1L的结合模式,并分析了该类化合物的构效关系。本研究为研发活性更好、选择性高的DOT1L小分子抑制剂提供了重要的线索。
Methyltransferases of epigenetic modification play a key role in regulating transcription and are closely related with in the genesis,development and prognosis of human cancer,which have become a promising target for cancer therapy.DOT1 L is a protein methyltransferase to methylate histone H3 on Lysine 79,which is required for the development and maintenance of MLL-rearranged mixed lineage leukemia.Here,we report the development of a target-specific score function SAM-score for S-adenosylmethionine(SAM) dependent methyltransferase targets and the discovery of novel DOTIL inhibitor DCD-17 based on SAM-score.DCD-17 is non-nucleoside DOTIL inhibitor with an IC_(50) value of 4.5 μM and exhibits significant selectivity over other SAM-dependent methyltransferases.In cellular studies,DCD-17 inhibited MLL-rearranged cell proliferation with EC_(50) value of 21.8 μM.Furthermore,the putative binding modes of DCD-17 and its analogs obtained by molecular docking and their structure-activity relationships were analyzed,which may assist future development DOT1 L inhibitors with better potency and selectivity profile.
Methyltransferases of epigenetic modification play a key role in regulating transcription and are closely related with in the genesis,development and prognosis of human cancer,which have become a promising target for cancer therapy.DOT1 L is a protein methyltransferase to methylate histone H3 on Lysine 79,which is required for the development and maintenance of MLL-rearranged mixed lineage leukemia.Here,we report the development of a target-specific score function SAM-score for S-adenosylmethionine(SAM) dependent methyltransferase targets and the discovery of novel DOTIL inhibitor DCD-17 based on SAM-score.DCD-17 is non-nucleoside DOTIL inhibitor with an IC_(50) value of 4.5 μM and exhibits significant selectivity over other SAM-dependent methyltransferases.In cellular studies,DCD-17 inhibited MLL-rearranged cell proliferation with EC_(50) value of 21.8 μM.Furthermore,the putative binding modes of DCD-17 and its analogs obtained by molecular docking and their structure-activity relationships were analyzed,which may assist future development DOT1 L inhibitors with better potency and selectivity profile.
引文
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[2]Xue,M.;Zheng,M.;Xiong,B.et al.J.Chem.Inf.Model 2010,50:1378-86.