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

Yiyou Huang, Xin Liu, Deyan Wu, Guihua Tang, Zengwei Lai, Xuehua Zheng, Sheng Yin, Hai-Bin Luo

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 11 nM and 90 nM, 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 selaginpulvilines 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.