title: In silico Analysis and Experimental Validation of Lignan Extracts from Kadsura longipedunculata for Potential 5-HT1AR Agonists.
abstract: OBJECTIVE
  Kadsura longipedunculata (KL) has been widely used for the treatment of insomnia in traditional Chinese medicine. The aim of this study was to explore the mechanism of the sedative and hypnotic effects of KL.
  
  
  METHODS
  The content of KL was evaluated by HPLC-TOF-MS, and a potential target was found and used to construct its 3D structure to screen for potential ligands among the compounds in KL by using bioinformatics analysis, including similarity ensemble approach (SEA) docking, homology modeling, molecular docking and ligand-based pharmacophore. The PCPA-induced insomnia rat model was then applied to confirm the potential targets related to the sedative effects of KL by performing the forced swimming test (FST), the tail suspension test (TST) and the measurement of target-related proteins using western blotting and immunofluorescence.
  
  
  RESULTS
  Bioinformatics analysis showed that most of lignan compounds in KL were optimal ligands for the 5-HT1A receptor (5-HT1AR), and they were found to be potential targets related to sedative effects; the main lignan content of KL extracts was characterized by HPLC-TOF-MS, with 7 proposed lignans detected. Administration of KL could significantly reduce FST and TST immobility time in the PCPA-induced 5HT-depleted insomnia rat model. The expressions of proteins related to the 5-HT1AR pathway were regulated by extracts of KL in a concentration-dependent manner, indicating that extracts of KL had 5-HT1AR agonist-like effects.
  
  
  CONCLUSIONS
  In silico analysis and experimental validation together demonstrated that lignan extracts from KL can target 5-HT1AR in insomniac rats, which could shed light on its use as a potential 5-HT1AR agonist drug.
authors.affiliation: Key Laboratory of Structure-Based Drug Design and Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang, 110016, China.
authors.forename: Yaxin
authors.initials: Y
authors.lastname: Zheng
authors.affiliation: Key Laboratory of Structure-Based Drug Design and Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang, 110016, China.
authors.forename: Jiming
authors.initials: J
authors.lastname: Wu
authors.affiliation: School of Pharmacy, China Medical University, Shenyang, 110122, China.
authors.forename: Xuesong
authors.initials: X
authors.lastname: Feng
authors.affiliation: School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang, 110016, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Jia
authors.affiliation: Key Laboratory of Structure-Based Drug Design and Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang, 110016, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Huang
authors.affiliation: Animal Center, Shenyang Pharmaceutical University, Shenyang, 110016, China.
authors.forename: Zhihui
authors.initials: Z
authors.lastname: Hao
authors.affiliation: School of Life Science, Shenyang Pharmaceutical University, Shenyang, 110016, China.
authors.forename: Songyan
authors.initials: S
authors.lastname: Zhao
authors.affiliation: Key Laboratory of Structure-Based Drug Design and Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang, 110016, China.
authors.forename: Jinhui
authors.initials: J
authors.lastname: Wang
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002851:Chromatography, High Pressure Liquid; D003198:Computer Simulation; D004365:Drugs, Chinese Herbal / Q000494:pharmacology*; D005260:Female; D010134:Fenclonine / Q000633:toxicity; D005455:Fluorescent Antibody Technique; D005638:Fruit / Q000737:chemistry; D019417:Hindlimb Suspension; D006993:Hypnotics and Sedatives / Q000494:pharmacology*; D032135:Kadsura / Q000737:chemistry*; D008958:Models, Molecular; D011487:Protein Conformation; D051381:Rats; D017207:Rats, Sprague-Dawley; D044282:Receptor, Serotonin, 5-HT1A / Q000737:chemistry* / Q000378:metabolism; D058825:Serotonin 5-HT1 Receptor Agonists / Q000494:pharmacology*; D007319:Sleep Initiation and Maintenance Disorders / Q000139:chemically induced / Q000188:drug therapy*; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D013550:Swimming; D054928:Validation Studies as Topic
chemical_list: D004365:Drugs, Chinese Herbal; D006993:Hypnotics and Sedatives; D058825:Serotonin 5-HT1 Receptor Agonists; D044282:Receptor, Serotonin, 5-HT1A; D010134:Fenclonine