Application of oxime-diversification to optimize ligand interactions within a cryptic pocket of the polo-like kinase 1 polo-box domain

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:26

Article

Zhao, Xue Zhi¹  Hymel, David¹  Burke, Terrence R., Jr.¹ 

[1] NCI, Biol Chem Lab, Ctr Canc Res, NIH, Frederick, MD 21702 USA

关键词: Plk1 polo-box domain;    Ligand optimization;    Oxime ligation;    Cryptic binding pocket;   

DOI  :  10.1016/j.bmcl.2016.08.098

来源: Elsevier

【 摘 要 】

By a process involving initial screening of a set of 87 aldehydes using an oxime ligation-based strategy, we were able to achieve a several-fold affinity enhancement over one of the most potent previously known polo-like kinase 1 (Plk1) polo-box domain (PBD) binding inhibitors. This improved binding may result by accessing a newly identified auxiliary region proximal to a key hydrophobic cryptic pocket on the surface of the protein. Our findings could have general applicability to the design of PBD-binding antagonists. Published by Elsevier Ltd.

【 授权许可】

Free