Structure-aided optimization of kinase inhibitors derived from alsterpaullone
Structure-aided optimization of kinase inhibitors derived from alsterpaullone
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DOI：
10.1002/cbic.200400099
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发表时间：
2005-03-01
期刊：
影响因子：
3.2
通讯作者：
Lemcke, T
中科院分区：
文献类型：
--
作者：
Kunick, C;Zeng, ZH;Lemcke, T
为了进行计算机辅助设计的新的alsterpaullone衍生物，附近的入口处的ATP结合位点进行了扫描的区域，可能是有用的锚定点额外的蛋白质-配体相互作用。基于在CDK 1/细胞周期蛋白B同源模型中alsterpaullone的比对，将取代基连接到母体支架的2-位以使得能够在鉴定的区域内接触。设计结构的合成揭示了三个衍生物（3-5），其具有与阿司特保罗酮类似的激酶抑制活性。新的2-氰乙基阿司特保罗酮（7）被证明是所描述的最有效的保罗酮，其对CDK 1/细胞周期蛋白B和GSK-3 β的抑制浓度在皮摩尔范围内。
In order to perform computer-aided design of novel alsterpaullone derivatives, the vicinity of the entrance to the ATP-binding site was scanned for areas that could be useful as anchoring points for additional protein-ligand interactions. Based on the alignment of alsterpaullone in a CDK1/cyclin B homology model, substituents were attached to the 2-position of the parent scaffold to enable contacts within the identified areas. Synthesis of the designed structures revealed three derivatives (3-5) with kinase-inhibitory activity similar to alsterpaullone. The novel 2-cyanoethylalsterpaullone (7) proved to be the most potent paullone described so for, exhibiting inhibitory concentrations for CDK1/ cyclin B and GSK-3 beta in the picomolar range.