Feng Xiaoqing, Wang Huanchen, Ye Mengchun, Xu Xue-Tao, Xu Ying, Yang Wenzhe, Zhang Han-Ting, Song Guoqiang, Ke Hengming
School of Pharmaceutical Engineering and Life Sciences , Changzhou University , Changzhou , Jiangsu 213164 , P. R. China.
Department of Biochemistry and Biophysics and Lineberger Comprehensive Cancer Center , The University of North Carolina at Chapel Hill , Chapel Hill , North Carolina 27599-7260 , United States.
Biochemistry. 2018 Jul 31;57(30):4518-4525. doi: 10.1021/acs.biochem.8b00336. Epub 2018 Jul 17.
Inhibitors of phosphodiesterases (PDEs) have been widely studied as therapeutics for the treatment of human diseases, but improvement of inhibitor selectivity is still desirable for the 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 IC values of 12 and 20 nM for the catalytic domains of PDE4D2 and PDE4B2B, respectively, selectivity several thousand-fold greater than those of 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)-Zl-n-91 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 the design of PDE4 selective inhibitors.
磷酸二酯酶（PDEs）抑制剂作为治疗人类疾病的药物已得到广泛研究，但为提高抑制剂效力，仍需要提高抑制剂的选择性。在此，我们报告鉴定出一个含水亚口袋作为PDE4特异性的抑制剂结合口袋。我们针对该口袋进行设计并合成了PDE4抑制剂Zl-n-91的两种对映体。（S）-Zl-n-91对映体对PDE4D2和PDE4B2B催化结构域的IC值分别为12和20 nM，选择性比其他PDE家族高数千倍，并且具有强大的神经保护活性。PDE4D2催化结构域与每种Zl-n-91对映体复合物的晶体结构表明，（S）-Zl-n-91而非（R）-Zl-n-91与口袋中的结合水形成了氢键，从而解释了其更高的亲和力。PDE家族之间的结构叠加表明，这个含水亚口袋是PDE4特有的，因此对于设计PDE4选择性抑制剂具有重要价值。
