Structural Biology-Inspired Discovery of Novel KRAS-PDEδ Inhibitors

  • J Med Chem. 2017 Nov 22;60(22):9400-9406. doi: 10.1021/acs.jmedchem.7b01243.
Yan Jiang  1 ,  Chunlin Zhuang  1 ,  Long Chen  1 ,  Junjie Lu  1 ,  Guoqiang Dong  1 ,  Zhenyuan Miao  1 ,  Wannian Zhang  1 ,  Jian Li  2 ,  Chunquan Sheng  1
Affiliations
  • 1. School of Pharmacy, Second Military Medical University , Shanghai 200433, China.
  • 2. School of Pharmacy, East China University of Science & Technology , Shanghai 200237, China.
PMID: 28929751 DOI: 10.1021/acs.jmedchem.7b01243
Abstract

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.

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