PLK1激酶KD的别构抑制剂
详细信息 查看官网全文
- 英文论文题名：The allosteric inhibitors for PLK1 KD
- 论文作者：刘莹 ; 云泰康翔 ; 覃覃 ; 来鲁华
- 英文论文作者：Ying Liu ; Taikangxiang Yun ; Tan Qin ; Luhua Lai ; College of Chemistry and Molecular Engineering ; Peking University ; Academy for Advanced Interdisciplinary Studies ; Peking University
- 年：2016
- 作者机构：北京大学化学与分子工程学院;北京大学前沿交叉学科研究院;
- 论文关键词：PLK1 ; KD ; 新位点 ; 别构 ; 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：R91
- 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：141k
- 原文格式：D
- 会议级别：全国
摘要
Polo-like kinase 1(PLK1)是一种丝氨酸/苏氨酸蛋白激酶,在有丝分裂中发挥重要作用。PLK1由相互抑制的结构域Kinase domain(KD)和Polo-box domain(PBD)组成。KD是催化结构域,其抑制剂具有抗肿瘤等功能【1】。已报道的PLK1 KD抑制剂主要作用于ATP结合位点,这些ATP竞争型抑制剂活性高但选择性低、毒副作用大,寻找PLK1的非ATP竞争型抑制剂有望克服上述缺点。我们开展PLK1 KD的非ATP竞争型抑制剂探索,应用本实验室研发的Cavity程序【2】对于PLK1 KD的表面进行分析,预测出两个可药性结合位点:除了ATP结合位点外,还有一个新的位点。我们对新位点进行分子对接虚拟筛选,购买打分排在前列的近两百个有机小分子,通过全长PLK1酶活测定,发现四个具有抑制活性的化合物。对活性最好的小分子进一步研究发现:1)其对于KD的酶活抑制与ATP不存在竞争关系;2)其对于KD的结合与ATP或底物不存在竞争关系【3】。这表明新位点是KD的别构位点,有活性的小分子是PLK1 KD的別构调控抑制剂。这些工作为获得新理念的PLK1抑制剂奠定了基础。
Polo-like kinase 1(PLK1) is an evolutionarily conserved serine/threonine kinase,and its N-terminal kinase domain(KD) controls cell signaling through phosphorylation.Inhibitors of PLK1 are potential anticancer drugs.Most known PLK1 KD inhibitors are ATP-competitive compounds,which may suffer from low selectivity.In this study we discovered novel non-ATP-competitive PLK1 KD inhibitors by virtual screening and experimental studies.A new potential binding site in PLK1 KD was identified by using the protein binding site detection program Cavity.The identified site was successfully used to discover non-ATP-competitive PLK1 inhibitors.Further studies indicated that the most potential compound does not compete with ATP or the peptide substrate,which is allosteric inhibitor for PLK1 KD.The new binding site is an allosteric pocket of PLK1 KD and can be used to search for other potential inhibitors.
Polo-like kinase 1(PLK1) is an evolutionarily conserved serine/threonine kinase,and its N-terminal kinase domain(KD) controls cell signaling through phosphorylation.Inhibitors of PLK1 are potential anticancer drugs.Most known PLK1 KD inhibitors are ATP-competitive compounds,which may suffer from low selectivity.In this study we discovered novel non-ATP-competitive PLK1 KD inhibitors by virtual screening and experimental studies.A new potential binding site in PLK1 KD was identified by using the protein binding site detection program Cavity.The identified site was successfully used to discover non-ATP-competitive PLK1 inhibitors.Further studies indicated that the most potential compound does not compete with ATP or the peptide substrate,which is allosteric inhibitor for PLK1 KD.The new binding site is an allosteric pocket of PLK1 KD and can be used to search for other potential inhibitors.
引文
[1]Lee,K.;Burke,T.;Park,J.,Bang,J.;Lee,E.Trends Pharmacol.Sci.2015,36(12):858.
[2]Yuan,Y.;Pei,J.;Lai,L.J.Chem.Inf.Model.2011,51(5):1083.
[3]Yun,T.;Qin,T.;Liu,Y.;Lai,L.ChemMedChem 2016,11(7):713.
[2]Yuan,Y.;Pei,J.;Lai,L.J.Chem.Inf.Model.2011,51(5):1083.
[3]Yun,T.;Qin,T.;Liu,Y.;Lai,L.ChemMedChem 2016,11(7):713.