Vangrevelinghe Eric, Zimmermann Kaspar, Schoepfer Joseph, Portmann Robert, Fabbro Doriano, Furet Pascal
Oncology Research, Novartis Pharma AG, 4002 Basle, Switzerland.
J Med Chem. 2003 Jun 19;46(13):2656-62. doi: 10.1021/jm030827e.
To assess the potential of protein kinase CK2 as a target for developing new antitumor agents, we have undertaken a search for inhibitors of this enzyme. As part of this effort, we report here the discovery of the potent and selective CK2 inhibitor (5-oxo-5,6-dihydroindolo[1,2-a]quinazolin-7-yl)acetic acid. We identified this inhibitor of a novel structural type by high-throughput docking of our corporate compound collection in the ATP binding site of a homology model of human CK2, using an appropriate protocol. The synthesis of the inhibitor as well as that of related analogues whose CK2 inhibitory activities give support to the binding mode proposed by the docking program is described. The results obtained suggest that virtual screening of a 3D database by molecular docking is a useful approach for lead finding provided that adapted postdocking filtering and reranking procedures are applied to the primary hit list.
为了评估蛋白激酶CK2作为开发新型抗肿瘤药物靶点的潜力，我们开展了对该酶抑制剂的研究。作为这项工作的一部分，我们在此报告强效且选择性的CK2抑制剂（5-氧代-5,6-二氢吲哚并[1,2-a]喹唑啉-7-基）乙酸的发现。我们通过使用适当的方案，将公司化合物库在人CK2同源模型的ATP结合位点进行高通量对接，鉴定出这种新型结构类型的抑制剂。描述了该抑制剂以及相关类似物的合成，其CK2抑制活性支持对接程序提出的结合模式。获得的结果表明，通过分子对接对三维数据库进行虚拟筛选是一种有用的先导化合物发现方法，前提是对初步命中列表应用合适的对接后筛选和重新排名程序。
