本项目针对Hsp90-Cdc37相互作用的两个核心问题开展研究：1）准确解析二者相互作用的分子机制，建立表征模型；2）设计并获得能够高效干扰其相互作用的短肽及小分子调控剂。在前期研究基础和已有平台的支撑下，综合运用药物化学、结构生物学、信息学、计算机辅助药物设计学等多种技术手段，完成如下工作：1）从分子层面上挖掘Hsp90-Cdc37在动态相互作用过程中的关键分子事件及结合热区，解析其结构及空间特征；2）发现高亲和力的短肽并通过合成方法学进行构象及理化性质优化；3）将Hsp90-Cdc37结合热区进行区域化分割，针对每个区域获得高配体效率的片段，以优化短肽为模板，以采用基于分子片段的设计策略进行骨架重组，获得高亲和小分子调控剂，完成分子由肽向非肽的过渡，最终获得具有良好类药性的Hsp90-Cdc37特异性调控剂。

In this application, our aim is to solve two basic problems in the mechanism study of Hsp90-Cdc37 protein-protein interaction and the modulator design: 1) the elucidation of the molecular recognition between the two proteins; 2) the design of modulators with high binding affinity. By combination of medicinal chemistry, structure biology, molecular informatics, computer aided drug design, we will finish the work listed below: 1) describe the key event in the interaction mode of Hsp90-Cdc37 in the molecular level and confirm the binding hotspots of the two proteins; 2) the discovery and optimization of peptides with high affinity to the PPI; 3)we will separate the binding groove of Hsp90-Cdc37 based on the characteristics of hotspots and find active fragment to realize the chemical space of hotspots, followed by a combination of the fragments guided by the structure of PPI. Through this application, we will finish the transition of the scaffold of the modulators from peptide to non-peptide, and achieve novel compounds with good binding affinity, selectivity targeting Hsp90-Cdc37 interaction.