title: Discovery and modelling studies of natural ingredients from Gaultheria yunnanensis (FRANCH.) against phosphodiesterase-4.
abstract: Phosphodiesterase-4 (PDE4) is an anti-inflammatory target for treatment of asthma and chronic obstructive pulmonary disease (COPD). Here, we report the isolation and characterization of 13 compounds (G1-G13) by bioassay-guided fractionation of the ethyl acetate extraction of Gaultheria yunnanensis (FRANCH.), one of which pentacyclic triterpene (G1) has never been reported. Four of them (G1, G2, G4, and G5) inhibit PDE4 with the IC50 values < 20 μM and G1 is the most potent ingredient with an IC50 of 245 nM and moderate selectivity over other PDE families. Molecular dynamics simulations suggest that G1 forms a hydrogen bond with Asn362, in addition to the hydrogen bond with Gln369 and π-π interactions with Phe372, which are commonly observed in the binding of most PDE4 inhibitors. The calculated binding free energies for the interactions of PDE4-G1 and PDE4-G2 are -19.4 and -18.8 kcal/mol, in consistence with the bioassay that G1 and G2 have IC50 of 245 nM and 542 nM, respectively. The modelling results of these active compounds may aid the rational design of novel PDE4 inhibitors as anti-inflammatory agents.
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, PR China.
authors.forename: Ying-Hong
authors.initials: YH
authors.lastname: Cai
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, PR China.
authors.forename: Yanqiong
authors.initials: Y
authors.lastname: Guo
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, PR China.
authors.forename: Zhe
authors.initials: Z
authors.lastname: Li
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, PR China.
authors.forename: Deyang
authors.initials: D
authors.lastname: Wu
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, PR China.
authors.forename: Xiruo
authors.initials: X
authors.lastname: Li
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, PR China.
authors.forename: Heng
authors.initials: H
authors.lastname: Zhang
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, PR China.
authors.forename: Junjie
authors.initials: J
authors.lastname: Yang
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, PR China.
authors.forename: Heng
authors.initials: H
authors.lastname: Lu
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, PR China.
authors.forename: Zhaowei
authors.initials: Z
authors.lastname: Sun
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, PR China.
authors.forename: Hai-Bin
authors.initials: HB
authors.lastname: Luo
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, PR China. Electronic address: yinsh2@mail.sysu.edu.cn.
authors.forename: Sheng
authors.initials: S
authors.lastname: Yin
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, PR China. Electronic address: wyinuo3@mail.sysu.edu.cn.
authors.forename: Yinuo
authors.initials: Y
authors.lastname: Wu
mesh_terms: D001688:Biological Products / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D031282:Gaultheria / Q000737:chemistry*; D006860:Hydrogen Bonding; D008958:Models, Molecular; D015394:Molecular Structure; D058988:Phosphodiesterase 4 Inhibitors / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D010957:Plasmids; D011994:Recombinant Proteins / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D001688:Biological Products; D058988:Phosphodiesterase 4 Inhibitors; D011994:Recombinant Proteins; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4
keywords: Anti-inflammatory agents; Gaultheria yunnanensis (FRANCH.); Phosphodiesterase-4