Defining Cdk5 ligand chemical space with small molecule inhibitors of Tau phosphorylation
Defining Cdk5 ligand chemical space with small molecule inhibitors of Tau phosphorylation
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DOI：
10.1016/j.chembiol.2005.05.011
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发表时间：
2005-07-01
影响因子：
--
通讯作者：
Kosik, KS
中科院分区：
文献类型：
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作者：
Ahn, JS;Radhakrishnan, ML;Kosik, KS
细胞周期蛋白依赖性激酶5（Cdk5）被广泛认为是多种神经系统疾病的可能靶点。归因于Cdk5的一个病理作用是tau的异常磷酸化，其可导致称为神经元缠结的神经元内含物。针对Cdk5介导的tau磷酸化的抑制剂的高通量筛选产生了具有不同作用机制的三种化合物。一种化合物与ATP竞争，并对Cdk5 ATP结合口袋具有高亲和力。第二种化合物也与ATP竞争，与tau无竞争性，并且（在这类抑制剂中是唯一的）取代相邻的氨基酸残基，为硝基苯基腾出空间。第三种化合物不与ATP竞争，但在低浓度的tau下与tau竞争。来自两个ATP竞争者的共晶沿着三个其他ATP竞争者的共晶的SAR和电荷优化映射出填充和适当充电ATP结合口袋的不同区域的重要性。总之，该分析显示了Cdk5的结构如何约束潜在抑制剂的空间，并揭示了所有结构中未填充的口袋。这些先导化合物可能成为基于结构的药物设计的起点，以获得更有效和更有选择性的抑制剂。
Cyclin-dependent kinase 5 (Cdk5) is widely viewed as a possible target for a wide variety of neurological disorders. One pathological role attributed to Cdk5 Is the abnormal phosphorylation of tau that may lead to the neuronal inclusions known as neurofibrillary tangles. A high through-put screen for inhibitors of Cdk5-mediated phosphorylation of tau resulted in three compounds with distinct mechanisms of action. One compound is competitive with ATP and has a high affinity for the Cdk5 ATP binding pocket. The second compound also competes with ATP, is noncompetitive with tau, and (uniquely among this class of inhibitors) displaces adjacent amino acid residues to make room for the nitrophenyl group. A third compound did not compete with ATP, but did compete with tau at low concentrations of tau. The SAR and charge optimization derived from cocrystals of the two ATP competitors along with cocrystals of three other ATP competitors map out the importance of filling and properly charging different regions of the ATP binding pocket. Taken together, this analysis shows how the structure of Cdk5 constrains the space of potential inhibitors and reveals a pocket unfilled in all of the structures. These leads could be a starting point for structure-based drug design of more potent and selective inhibitors.