Affordable Access

deepdyve-link
Publisher Website

The discovery, complex crystal structure, and recognition mechanism of a novel natural PDE4 inhibitor from Selaginella pulvinata.

Authors
  • Huang, Yiyou1
  • Liu, Xin1
  • Wu, Deyan1
  • Tang, Guihua1
  • Lai, Zengwei1
  • Zheng, Xuehua2
  • Yin, Sheng3
  • Luo, Hai-Bin4
  • 1 School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, China. , (China)
  • 2 School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou 511436, China. Electronic address: [email protected] , (China)
  • 3 School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, China. Electronic address: [email protected] , (China)
  • 4 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: [email protected] , (China)
Type
Published Article
Journal
Biochemical pharmacology
Publisher
New York, NY : Elsevier Science Inc
Publication Date
Apr 15, 2017
Volume
130
Pages
51–59
Identifiers
DOI: 10.1016/j.bcp.2017.01.016
PMID: 28159622
Source
Medline
Keywords
License
Unknown

Abstract

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 IC50 11nM 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.

Report this publication

Statistics

Seen <100 times