Structure-based virtual screening and optimization of modulators targeting Hsp90-Cdc37 interaction
Structure-based virtual screening and optimization of modulators targeting Hsp90-Cdc37 interaction
复制标题
基于结构的虚拟筛选和针对 Hsp90-Cdc37 相互作用的调节剂的优化。
DOI：
10.1016/j.ejmech.2017.04.074
复制
发表时间：
2017-08-18
影响因子：
6.7
通讯作者：
Xu, Xiao-Li
中科院分区：
文献类型：
--
作者：
Wang, Lei;Li, Li;Xu, Xiao-Li
Identification of novel Hsp90 inhibitors to disrupt Hsp90-Cdc37 protein-protein interaction (PPI) could be an alternative strategy to achieve Hsp90 inhibition. In this paper, a series of small molecules targeting Hsp90-Cdc37 complex are addressed and characterized. The molecules' key characters are determined by utilizing a structure-based virtual screening workflow, derivatives synthesis, and biological evaluation. Structural optimization and structure activity relationship (SAR) analysis were then carried out on the virtual hit of VS-8 with potent activity, which resulted in the discovery of compound 10 as a more potent regulator of Hsp90-Cdc37 interaction with a promising inhibitory effect (IC50 = 27 mu M), a moderate binding capacity (K-D = 40 mu M) and a preferable antiproliferative activity against several cancer lines including MCF-7, SKBR3 and A549 cell lines (IC50 = 26 mu M,15 M and 38 mu M respectively). All the data suggest that compound 10 exhibits moderate inhibitory effect on Hsp90-Cdc37 and could be regard as a first evidence of a non-natural compound targeting Hsp90-Cdc37 PPI. (C) 2017 Elsevier Masson SAS. All rights reserved.
