期刊
BIOTECHNOLOGY JOURNAL
卷 6, 期 7, 页码 871-881出版社
WILEY-BLACKWELL
DOI: 10.1002/biot.201100139
关键词
CDK5; Molecular dynamics; Protein-protein interaction inhibitor; Virtural alanine scanning; Virtual screening
资金
- Region Bretagne (ARED) [3358]
- CNRS
- Association pour la Recherche contre le Cancer (ARC) [ARC3889]
The lack of selectivity of all existing ATPcompetitive inhibitors for a single cyclin-dependent kinase (CDK) has led us to redirect the structure-based molecule design from targeting the classic ATP-binding pocket in CDK5 toward the CDK5/p25 interface. The aim was to seek novel inhibition mechanisms to interrupt protein-protein interactions. A combined strategy of alanine-scanning calculations for locating binding sites, virtual screening for small molecules, molecular dynamics simulations for examining the binding stability of virtual screening hits and bio-assays for testing the level of inhibition was set up and used to explore novel inhibitors capable of interrupting the interactions between the proteins, and consequently of inhibiting the kinase activity. Two compounds were shown to inhibit the complex formation between CDK5 and p25 through p25 binding. They could open avenues for the discovery of new types of structures that prevent interactions between CDK5 and p25 or other CDK and activator proteins, and, more importantly, provide leads in the development of selective inhibitors among CDKs.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据