Structural Characterization of LRRK2 Inhibitors
Structural Characterization of LRRK2 Inhibitors
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DOI：
10.1021/jm5018779
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发表时间：
2015-05-14
影响因子：
7.3
通讯作者：
Kortholt, Arjan
中科院分区：
文献类型：
--
作者：
Gilsbach, Bernd K.;Messias, Ana C.;Kortholt, Arjan
激酶抑制被认为是LRRK2介导的帕金森病(PD)的重要治疗靶点。许多LRRK2激酶抑制剂已被报道，但尚未优化，以便有资格作为治疗该疾病的候选药物。为了开始这类抑制剂的结构和功能分析，我们将DictyostelialRoco4的活性部位突变为类似于LRRK2。在这里，我们展示了饱和转移差(STD)核磁共振和两个有效的体外抑制剂，LRRK2-IN-1和化合物19，与突变的Roco4的第一共晶结构。我们的数据表明，该系统可以作为一个很好的工具来表征和优化LRRK2抑制剂的结构，使用X射线结晶学和核磁共振波谱。
Kinase inhibition is considered to be an important therapeutic target for LRRK2 mediated Parkinson's disease (PD). Many LRRK2 kinase inhibitors have been reported but have yet to be optimized in order to qualify as drug candidates for the treatment of the disease. In order to start a structure-function analysis of such inhibitors, we mutated the active site of Dictyostelium Roco4 kinase to resemble LRRK2. Here, we show saturation transfer difference (STD) NMR and the first cocrystal structures of two potent in vitro inhibitors, LRRK2-IN-1 and compound 19, with mutated Roco4. Our data demonstrate that this system can serve as an excellent tool for the structural characterization and optimization of LRRK2 inhibitors using X-ray crystallography and NMR spectroscopy.