Multiple and single binding modes of fragment-like kinase inhibitors revealed by molecular modeling, residue type-selective protonation, and nuclear overhauser effects
Multiple and single binding modes of fragment-like kinase inhibitors revealed by molecular modeling, residue type-selective protonation, and nuclear overhauser effects
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DOI：
10.1021/jm800747w
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发表时间：
2008-10-09
影响因子：
7.3
通讯作者：
Tokarski, John
中科院分区：
文献类型：
--
作者：
Constantine, Keith L.;Mueller, Luciano;Tokarski, John
丝裂原活化蛋白激酶活化蛋白激酶2(MK2)的片段样抑制物包括5-羟基异喹啉(IC(50)，类似于85mU M)。模型研究确定了该化合物的四种可能的结合模式。用选择性质子化的MK2与5-羟基异喹啉形成的络合物获得的二维(1)H-(1)H NOESY数据表明，四种预测的结合模式中的两种被很好地填充。第二个小的异喹啉随后被证明以单一模式结合。使用这种一般方法的核磁共振和建模研究有望促进“支架跳跃”和结构指导下的片段样激酶抑制物核心的阐述。
Fragment-like inhibitors of mitogen-activated protein kinase-activated protein kinase 2 (MK2) include 5-hydroxyisoquinoline (IC(50) similar to 85 mu M). Modeling studies identified four possible binding modes for this compound. Two-dimensional (1)H-(1)H NOESY data obtained with selectively protonated samples of MK2 in complex with 5-hydroxyisoquinoline demonstrated that two of the four predicted binding modes are well populated. A second small isoquinoline was subsequently shown to bind in a single mode. NMR and modeling studies using this general approach are expected to facilitate "scaffold hopping" and structure-guided elaborations of fragment-like kinase inhibitor cores.