Jiang Yan, Zhuang Chunlin, Chen Long, Lu Junjie, Dong Guoqiang, Miao Zhenyuan, Zhang Wannian, Li Jian, Sheng Chunquan
School of Pharmacy, Second Military Medical University , Shanghai 200433, China.
School of Pharmacy, East China University of Science & Technology , Shanghai 200237, China.
J Med Chem. 2017 Nov 22;60(22):9400-9406. doi: 10.1021/acs.jmedchem.7b01243. Epub 2017 Oct 3.
Structural biology is a powerful tool for investigating the stereospecific interactions between a protein and its ligand. Herein, an unprecedented chiral binding pattern was observed for inhibitors of KRAS-PDEδ interactions. Virtual screening and X-ray crystallography studies revealed that two enantiomers of a racemic inhibitor could bind at different sites. Fragment-based drug design was used to identify highly potent PDEδ inhibitors that can be used as promising lead compounds for target validation and antitumor drug development.
结构生物学是研究蛋白质与其配体之间立体特异性相互作用的有力工具。在此，观察到KRAS-PDEδ相互作用抑制剂呈现出前所未有的手性结合模式。虚拟筛选和X射线晶体学研究表明，外消旋抑制剂的两种对映体可在不同位点结合。基于片段的药物设计用于鉴定高效的PDEδ抑制剂，这些抑制剂可作为用于靶点验证和抗肿瘤药物开发的有前景的先导化合物。
