Network pharmacology-based and molecular docking prediction of the active ingredients and mechanism of ZaoRenDiHuang capsules for application in insomnia treatment

BACKGROUND The ZaoRenDiHuang (ZRDH) capsule is widely used in clinical practice and has significant therapeutic effects on insomnia. However, its active ingredients and mechanisms of action for insomnia remain unknown. In this study, network pharmacology was employed to elucidate the potential anti-insomnia mechanisms of ZRDH. METHODS The potential active ingredients of ZRDH were obtained from the Traditional Chinese Medicine Systems Pharmacology Database. Possible targets were predicted using SwissTargetPrediction tools. The insomnia-related targets were identified using the therapeutic target database, Drugbank database, Online Mendelian Inheritance in Man database, and gene-disease associations database. A compound-target-disease network was constructed using Cytoscape for visualization. Additionally, the protein functional annotation and identification of signaling pathways of potential targets were performed using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses using the Metascape platform. RESULTS In this study, 61 anti-insomnia components and 65 anti-insomnia targets of ZRDH were filtered through database mining. The drug-disease network was constructed with five key components. Sixty-five key targets were identified using topological analysis. Docking studies indicated that bioactive compounds could stably bind to the pockets of target proteins. Through data mining and network analysis, the GO terms and KEGG annotation suggested that the neuroactive ligand-receptor interaction, serotonergic synapse CAMP signaling, HIF-1a signaling, and toll-like receptor signaling pathways play vital roles against insomnia. CONCLUSION The potential mechanisms of ZRDH treatment for insomnia involve multiple components, targets, and pathways. These findings provide a reference for further investigations into the mechanisms underlying ZRDH treatment of insomnia.

[1]  Se Jin Park,et al.  Ameliorating effect of spinosin, a C-glycoside flavonoid, on scopolamine-induced memory impairment in mice , 2014, Pharmacology Biochemistry and Behavior.

[2]  Gary D. Bader,et al.  An automated method for finding molecular complexes in large protein interaction networks , 2003, BMC Bioinformatics.

[3]  Xue Xu,et al.  Network pharmacology-based prediction of the active ingredients and potential targets of Chinese herbal Radix Curcumae formula for application to cardiovascular disease. , 2013, Journal of ethnopharmacology.

[4]  C. Morin,et al.  Chronic insomnia , 2012, The Lancet.

[5]  G. Zammit.  Comparative Tolerability of Newer Agents for Insomnia , 2009, Drug safety.

[6]  R. Kessler,et al.  Sleep Problems, Comorbid Mental Disorders, and Role Functioning in the National Comorbidity Survey Replication , 2006, Biological Psychiatry.

[7]  Nadezhda T. Doncheva,et al.  Visualize omics data on networks with Omics Visualizer, a Cytoscape App , 2020, F1000Research.

[8]  Wei Zhou,et al.  TCMSP: a database of systems pharmacology for drug discovery from herbal medicines , 2014, Journal of Cheminformatics.

[9]  M. Zhuo,et al.  Sleep deprivation impairs cAMP signaling in the hippocampus , 2009, Nature.

[10]  S. Cui,et al.  Potentiating effect of spinosin, a C-glycoside flavonoid of Semen Ziziphi spinosae, on pentobarbital-induced sleep may be related to postsynaptic 5-HT(1A) receptors. , 2010, Phytomedicine : international journal of phytotherapy and phytopharmacology.

[11]  I. Fietze,et al.  Insomnia symptoms combined with nocturnal hypoxia associate with cardiovascular comorbidity in the European sleep apnea cohort (ESADA) , 2018, Sleep and Breathing.

[12]  N. Douglas,et al.  Randomized clinical effectiveness trial of nurse-administered small-group cognitive behavior therapy for persistent insomnia in general practice. , 2007, Sleep.

[13]  D. Gozal,et al.  Chronic sleep fragmentation induces endothelial dysfunction and structural vascular changes in mice. , 2014, Sleep.

[14]  Xi-jun Wang,et al.  Potential drug targets on insomnia and intervention effects of Jujuboside A through metabolic pathway analysis as revealed by UPLC/ESI-SYNAPT-HDMS coupled with pattern recognition approach. , 2012, Journal of proteomics.

[15]  Ajay N. Jain.  Surflex-Dock 2.1: Robust performance from ligand energetic modeling, ring flexibility, and knowledge-based search , 2007, J. Comput. Aided Mol. Des..

[16]  C. Reynolds,et al.  Epidemiological and clinical relevance of insomnia diagnosis algorithms according to the DSM-IV and the International Classification of Sleep Disorders (ICSD). , 2009, Sleep medicine.

[17]  J. Sarris,et al.  A systematic review of insomnia and complementary medicine. , 2011, Sleep medicine reviews.

[18]  M. Carskadon,et al.  Circadian rhythm sleep disorders: part I, basic principles, shift work and jet lag disorders. An American Academy of Sleep Medicine review. , 2007, Sleep.

[19]  Kai Spiegelhalder,et al.  Insomnia as a predictor of depression: a meta-analytic evaluation of longitudinal epidemiological studies. , 2011, Journal of affective disorders.

[20]  D. Hudgel,et al.  Prevalence and polysomnographic correlates of insomnia comorbid with medical disorders. , 2011, Sleep.

[21]  Olivier Michielin,et al.  SwissTargetPrediction: updated data and new features for efficient prediction of protein targets of small molecules , 2019, Nucleic Acids Res..

[22]  Yuanxiao Yang,et al.  GABA and 5-HT systems are implicated in the anxiolytic-like effect of spinosin in mice , 2015, Pharmacology Biochemistry and Behavior.

[23]  F. Sanz,et al.  The DisGeNET knowledge platform for disease genomics: 2019 update , 2019, Nucleic Acids Res..

[24]  Damian Szklarczyk,et al.  STRING v11: protein–protein association networks with increased coverage, supporting functional discovery in genome-wide experimental datasets , 2018, Nucleic Acids Res..

[25]  William C Clegern,et al.  Toll-like receptor 4 is a regulator of monocyte and electroencephalographic responses to sleep loss. , 2011, Sleep.

[26]  Chien-Yeh Hsu,et al.  Association of Sleep Duration and Insomnia Symptoms with Components of Metabolic Syndrome and Inflammation in Middle-Aged and Older Adults with Metabolic Syndrome in Taiwan , 2019, Nutrients.

[27]  Bo Zhang,et al.  Traditional Chinese medicine network pharmacology: theory, methodology and application: Traditional Chinese medicine network pharmacology: theory, methodology and application , 2014 .

[28]  Hua Yu,et al.  A Novel Chemometric Method for the Prediction of Human Oral Bioavailability , 2012, International journal of molecular sciences.

[29]  Wei Zhou,et al.  A novel systems pharmacology model for herbal medicine injection: a case using reduning injection , 2014, BMC Complementary and Alternative Medicine.

[30]  Rosanna Abbate,et al.  Insomnia and risk of cardiovascular disease: a meta-analysis , 2014, European journal of preventive cardiology.

[31]  H. Weiner,et al.  Microglial signatures and their role in health and disease , 2018, Nature Reviews Neuroscience.

[32]  G. Flores-Mateo,et al.  Effectiveness of Valerian on insomnia: a meta-analysis of randomized placebo-controlled trials. , 2010, Sleep medicine.

[33]  The Uniprot Consortium,et al.  UniProt: a hub for protein information , 2014, Nucleic Acids Res..

[34]  Sue J. Wilson,et al.  Antidepressants and Sleep , 2012, Drugs.

[35]  P. Lavie,et al.  Plasma vascular endothelial growth factor in sleep apnea syndrome: effects of nasal continuous positive air pressure treatment. , 2002, American journal of respiratory and critical care medicine.

[36]  N. Douglas,et al.  Randomized controlled clinical effectiveness trial of cognitive behavior therapy compared with treatment as usual for persistent insomnia in patients with cancer. , 2008, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[37]  X. Chen,et al.  TTD: Therapeutic Target Database , 2002, Nucleic Acids Res..

[38]  A. N. Jain,et al.  Hammerhead: fast, fully automated docking of flexible ligands to protein binding sites. , 1996, Chemistry & biology.

[39]  A. Hopkins.  Network pharmacology: the next paradigm in drug discovery. , 2008, Nature chemical biology.

[40]  R. Nahin,et al.  Insomnia, trouble sleeping, and complementary and alternative medicine: Analysis of the 2002 national health interview survey data. , 2006, Archives of internal medicine.

[41]  A. Scholey,et al.  Herbal medicine for depression, anxiety and insomnia: A review of psychopharmacology and clinical evidence , 2011, European Neuropsychopharmacology.

[42]  Núria Queralt-Rosinach,et al.  DisGeNET: a comprehensive platform integrating information on human disease-associated genes and variants , 2016, Nucleic Acids Res..

[43]  Damian Szklarczyk,et al.  The STRING database in 2017: quality-controlled protein–protein association networks, made broadly accessible , 2016, Nucleic Acids Res..

[44]  Olivier Michielin,et al.  Shaping the interaction landscape of bioactive molecules , 2013, Bioinform..

[45]  David S. Wishart,et al.  DrugBank 5.0: a major update to the DrugBank database for 2018 , 2017, Nucleic Acids Res..

[46]  Ya-Ling Huang,et al.  Association between toll-like receptor 4 expression and symptoms of major depressive disorder , 2015, Neuropsychiatric disease and treatment.

[47]  T. N. Bhat,et al.  The Protein Data Bank , 2000, Nucleic Acids Res..

[48]  Yong-He Zhang,et al.  Augmentative effect of spinosin on pentobarbital‐induced loss of righting reflex in mice associated with presynaptic 5‐HT1A receptor , 2012, The Journal of pharmacy and pharmacology.

[49]  J. Haythornthwaite,et al.  How do sleep disturbance and chronic pain inter-relate? Insights from the longitudinal and cognitive-behavioral clinical trials literature. , 2004, Sleep medicine reviews.

[50]  E. Bixler,et al.  Rebound insomnia after only brief and intermittent use of rapidly eliminated benzodiazepines , 1991, Clinical pharmacology and therapeutics.

[51]  Alexander R. Pico,et al.  Cytoscape Automation: empowering workflow-based network analysis , 2019, Genome Biology.

[52]  Qi-Hui Zhou,et al.  Suanzaoren Formulae for Insomnia: Updated Clinical Evidence and Possible Mechanisms , 2018, Front. Pharmacol..

[53]  C. Morin,et al.  Epidemiology of insomnia: prevalence, self-help treatments, consultations, and determinants of help-seeking behaviors. , 2006, Sleep medicine.

[54]  Brad T. Sherman,et al.  Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources , 2008, Nature Protocols.

[55]  T. Abel,et al.  Transiently Increasing cAMP Levels Selectively in Hippocampal Excitatory Neurons during Sleep Deprivation Prevents Memory Deficits Caused by Sleep Loss , 2014, The Journal of Neuroscience.

[56]  D. Luckenbaugh,et al.  Rapid antidepressant changes with sleep deprivation in major depressive disorder are associated with changes in vascular endothelial growth factor (VEGF): A pilot study , 2011, Brain Research Bulletin.

[57]  A. Hopkins.  Network pharmacology , 2007, Nature Biotechnology.

[58]  N. Vincent,et al.  Treatment preference and patient satisfaction in chronic insomnia. , 2001, Sleep.