The discovery, complex crystal structure, and recognition mechanism of a novel natural PDE4 inhibitor from Selaginella pulvinata.
Phosphodiesterase-4 (PDE4) is an important drug target for treatment of inflammation-related diseases. Till now, natural PDE4 inhibitors are rare and their co-crystal structures with PDE4 are hardly available. In the present study, selaginpulvilins K and L (1 and 2), two novel fluorene derivatives, were isolated from a traditional Chinese medicine Selaginella pulvinata and exhibited remarkable inhibition against phosphodiesterase-4D (PDE4D) at IC5011nM and 90nM, respectively. Compound 1 also showed a good selectivity across PDE families with the selective fold ranging from 30 to 909. To understand the recognition mechanism of selaginpulvilins towards PDE4, the crystal structure of PDE4D bound with 1 was successfully determined by the X-ray diffraction method and presented an unusual binding mode in which the stretched skeleton of the inhibitor bound shallowly to the active site but had interactions with multi sub-pockets, such as Q, HC, M, and S, especially strong interaction with the metal region. Assisted with molecular modeling, the structure-activity relationship and the selectivity of selaginpulvilins were also well explored, which would facilitate the future rational inhibitor design or structural optimizations.
School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, China.
Yiyou
Y
Huang
School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, China.
Xin
X
Liu
School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, China.
Deyan
D
Wu
School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, China.
Guihua
G
Tang
School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, China.
Zengwei
Z
Lai
School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou 511436, China. Electronic address: zhengxh23@gzhmu.edu.cn.
Xuehua
X
Zheng
School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, China. Electronic address: yinsh2@mail.sysu.edu.cn.
Sheng
S
Yin
School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, China; Collaborative Innovation Center of High Performance Computing, National University of Defense Technology, Changsha 410073, China. Electronic address: luohb77@mail.sysu.edu.cn.
Hai-Bin
HB
Luo
D018360:Crystallography, X-Ray; D015394:Molecular Structure; D058988:Phosphodiesterase 4 Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D032503:Selaginellaceae / Q000737:chemistry*
D058988:Phosphodiesterase 4 Inhibitors
Crystal structure; Natural inhibitor; Phosphodiesterase-4; Recognition mechanism; Selaginpulvilins K