title: Discovery of a New Class of Cathepsin K Inhibitors in Rhizoma Drynariae as Potential Candidates for the Treatment of Osteoporosis.
abstract: Rhizoma Drynariae(RD), as one of the most common clinically used folk medicines, has been reported to exert potent anti-osteoporotic activity. The bioactive ingredients and mechanisms that account for its bone protective effects are under active investigation. Here we adopt a novel in silico target fishing method to reveal the target profile of RD. Cathepsin K (Ctsk) is one of the cysteine proteases that is over-expressed in osteoclasts and accounts for the increase in bone resorption in metabolic bone disorders such as postmenopausal osteoporosis. It has been the focus of target based drug discovery in recent years. We have identified two components in RD, Kushennol F and Sophoraflavanone G, that can potentially interact with Ctsk. Biological studies were performed to verify the effects of these compounds on Ctsk and its related bone resorption process, which include the use of in vitro fluorescence-based Ctsk enzyme assay, bone resorption pit formation assay, as well as Receptor Activator of Nuclear factor κB (NF-κB) ligand (RANKL)-induced osteoclastogenesis using murine RAW264.7 cells. Finally, the binding mode and stability of these two compounds that interact with Ctsk were determined by molecular docking and dynamics methods. The results showed that the in silico target fishing method could successfully identify two components from RD that show inhibitory effects on the bone resorption process related to protease Ctsk.
authors.affiliation: Institute of Traditional Chinese Medicine & Natural Products, College of Pharmacy, Jinan University, Guangzhou 510632, China. qiu666@stu2014.jnu.edu.cn.
authors.forename: Zuo-Cheng
authors.initials: ZC
authors.lastname: Qiu
authors.affiliation: Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong, China. bcxldong@polyu.edu.hk.|Shenzhen Key Laboratory of Food Biological Safety Control, Shenzhen 518057, China. bcxldong@polyu.edu.hk.
authors.forename: Xiao-Li
authors.initials: XL
authors.lastname: Dong
authors.affiliation: Institute of Traditional Chinese Medicine & Natural Products, College of Pharmacy, Jinan University, Guangzhou 510632, China. daiyi1004@163.com.
authors.forename: Yi
authors.initials: Y
authors.lastname: Dai
authors.affiliation: Institute of Traditional Chinese Medicine & Natural Products, College of Pharmacy, Jinan University, Guangzhou 510632, China. xiaogk@yaolab.org.
authors.forename: Gao-Keng
authors.initials: GK
authors.lastname: Xiao
authors.affiliation: Translational Medicine R&D Center, Institute of Biomedical and Health Engineering, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518000, China. xl.wang@siat.ac.cn.
authors.forename: Xin-Luan
authors.initials: XL
authors.lastname: Wang
authors.affiliation: Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong, China. aguesses@yahoo.com.hk.
authors.forename: Ka-Chun
authors.initials: KC
authors.lastname: Wong
authors.affiliation: Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong, China. bcmswong@polyu.edu.hk.|State Key Laboratory of Chinese Medicine and Molecular Pharmacology (Incubation), Shenzhen 518057, China. bcmswong@polyu.edu.hk.
authors.forename: Man-Sau
authors.initials: MS
authors.lastname: Wong
authors.affiliation: Institute of Traditional Chinese Medicine & Natural Products, College of Pharmacy, Jinan University, Guangzhou 510632, China. tyaoxs@jnu.edu.cn.
authors.forename: Xin-Sheng
authors.initials: XS
authors.lastname: Yao
mesh_terms: D000818:Animals; D001862:Bone Resorption / Q000378:metabolism*; D056657:Cathepsin K / Q000037:antagonists & inhibitors*; D002460:Cell Line; D044950:Flavanones / Q000494:pharmacology; D006801:Humans; D051379:Mice; D062105:Molecular Docking Simulation; D010010:Osteoclasts / Q000378:metabolism*; D010012:Osteogenesis / Q000187:drug effects*; D010024:Osteoporosis / Q000188:drug therapy*; D028321:Plant Preparations / Q000494:pharmacology*; D029621:Polypodiaceae / Q000378:metabolism*; D053245:RANK Ligand / Q000378:metabolism; D000067996:RAW 264.7 Cells
chemical_list: D044950:Flavanones; D028321:Plant Preparations; D053245:RANK Ligand; C505689:Tnfsf11 protein, mouse; C064849:vexibinol; D056657:Cathepsin K
keywords: Cathepsin K; Kushennol F; RAW264.7 cells; Rhizoma Drynariae; Sophoraflavanone G; bone resorption; in silico target fishing; osteoclasts; osteoporosis