1. Identification of a PDE4-Specific Pocket for the Design of Selective Inhibitors
- Author
-
Wenzhe Yang, Xiaoqing Feng, Hengming Ke, Han-Ting Zhang, Mengchun Ye, Xue-Tao Xu, Guoqiang Song, Huanchen Wang, and Ying Xu
- Subjects
Male ,0301 basic medicine ,Stereochemistry ,Stereoisomerism ,Biochemistry ,Article ,03 medical and health sciences ,Memory ,Catalytic Domain ,Ic50 values ,Animals ,Humans ,Furans ,Mice, Inbred ICR ,Binding Sites ,Hydrogen bond ,Chemistry ,Phenyl Ethers ,Water ,Phosphodiesterase ,Hydrogen Bonding ,Cyclic nucleotide phosphodiesterases ,Cyclic Nucleotide Phosphodiesterases, Type 4 ,Molecular Docking Simulation ,030104 developmental biology ,Drug Design ,Water chemistry ,Phosphodiesterase 4 Inhibitors ,Enantiomer ,Selectivity ,Rolipram - Abstract
Inhibitors of phosphodiesterases (PDEs) have been widely studied as therapeutics for treatment of human diseases, but improvement on inhibitor selectivity is still desirable for enhancement of inhibitor potency. Here, we report identification of a water-containing subpocket as a PDE4-specific pocket for inhibitor binding. We designed against the pocket and synthesized two enantiomers of PDE4 inhibitor Zl-n-91. The (S)-Zl-n-91 enantiomer showed the IC50 values of 12 and 20 nM respectively for the catalytic domains of PDE4D2 and PDE4B2B, thousand folds of selectivity over other PDE families, and potent neuroprotection activities. Crystal structures of the PDE4D2 catalytic domain in complex with each Zl-n-91 enantiomer revealed that (S)-, but not (R)-Zl-n-91, formed a hydrogen bond with the bound water in the pocket, thus explaining its higher affinity. The structural superposition between the PDE families revealed that this water-containing subpocket is unique to PDE4 and thus valuable for design of PDE4 selective inhibitors.
- Published
- 2018