Rapid access to unexplored chemical space by ligand scanning around a ruthenium center: Discovery of potent and selective protein kinase inhibitors
Rapid access to unexplored chemical space by ligand scanning around a ruthenium center: Discovery of potent and selective protein kinase inhibitors
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DOI：
10.1021/ja055523r
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发表时间：
2006-01-25
影响因子：
15
通讯作者：
Meggers, E
中科院分区：
文献类型：
--
作者：
Bregman, H;Carroll, PJ;Meggers, E
发现具有独特生物活性的化合物的一个重要目标是开发用于合成具有限定三维形状的分子支架的方法。我们目前正在研究使用金属配合物来实现这一目标的范围。在这些化合物中，金属中心具有组织有机配体取向的作用，从而定义分子的整体形状。提出了一种策略，允许在寻找配体球的形状和功能基团介绍的ATP结合位点的蛋白激酶是互补的钌中心周围的配体的快速扫描。根据这种方法，我们已经确定八面体钌配合物作为蛋白激酶Pim 1，MSK 1和GSK 3 α的有效抑制剂。
An important objective for the discovery of compounds with unique biological activities is the development of methods for the synthesis of molecular scaffolds with defined three-dimensional shapes. We are currently investigating the scope of using metal complexes to accomplish this goal. In these compounds, the metal center has the role of organizing the orientation of the organic ligands, thus defining the overall shape of the molecule. A strategy is presented that allows a rapid scanning of ligands around a ruthenium center in the search for ligand spheres that are complementary in shape and functional group presentation to ATP binding sites of protein kinases. Following this approach, we have identified octahedral ruthenium complexes as potent inhibitors for the protein kinases Pim1, MSK1, and GSK3 alpha.