title: DrugGenEx-Net: a novel computational platform for systems pharmacology and gene expression-based drug repurposing.
abstract: BACKGROUND
  The targeting of disease-related proteins is important for drug discovery, and yet target-based discovery has not been fruitful. Contextualizing overall biological processes is critical to formulating successful drug-disease hypotheses. Network pharmacology helps to overcome target-based bottlenecks through systems biology analytics, such as protein-protein interaction (PPI) networks and pathway regulation.
  
  
  RESULTS
  We present a systems polypharmacology platform entitled DrugGenEx-Net (DGE-NET). DGE-NET predicts empirical drug-target (DT) interactions, integrates interaction pairs into a multi-tiered network analysis, and ultimately predicts disease-specific drug polypharmacology through systems-based gene expression analysis. Incorporation of established biological network annotations for protein target-disease, -signaling pathway, -molecular function, and protein-protein interactions enhances predicted DT effects on disease pathophysiology. Over 50 drug-disease and 100 drug-pathway predictions are validated. For example, the predicted systems pharmacology of the cholesterol-lowering agent ezetimibe corroborates its potential carcinogenicity. When disease-specific gene expression analysis is integrated, DGE-NET prioritizes known therapeutics/experimental drugs as well as their contra-indications. Proof-of-concept is established for immune-related rheumatoid arthritis and inflammatory bowel disease, as well as neuro-degenerative Alzheimer's and Parkinson's diseases.
  
  
  CONCLUSIONS
  DGE-NET is a novel computational method that predicting drug therapeutic and counter-therapeutic indications by uniquely integrating systems pharmacology with gene expression analysis. DGE-NET correctly predicts various drug-disease indications by linking the biological activity of drugs and diseases at multiple tiers of biological action, and is therefore a useful approach to identifying drug candidates for re-purposing.
authors.affiliation: Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington DC, 20057, USA.
authors.forename: Naiem T
authors.initials: NT
authors.lastname: Issa
authors.affiliation: Department of Biochemistry & Molecular Biology, Georgetown University, Washington DC, 20057, USA.
authors.forename: Jordan
authors.initials: J
authors.lastname: Kruger
authors.affiliation: Georgetown University Medical Center, Washington DC, 20057, USA.
authors.forename: Henri
authors.initials: H
authors.lastname: Wathieu
authors.affiliation: George Mason University, 4400 University Dr, Fairfax, VA, 22030, USA.
authors.forename: Rajarajan
authors.initials: R
authors.lastname: Raja
authors.affiliation: Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington DC, 20057, USA.|Department of Biochemistry & Molecular Biology, Georgetown University, Washington DC, 20057, USA.
authors.forename: Stephen W
authors.initials: SW
authors.lastname: Byers
authors.affiliation: Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington DC, 20057, USA. sd233@georgetown.edu.|Department of Biochemistry & Molecular Biology, Georgetown University, Washington DC, 20057, USA. sd233@georgetown.edu.
authors.forename: Sivanesan
authors.initials: S
authors.lastname: Dakshanamurthy
mesh_terms: D019295:Computational Biology / Q000379:methods*; D019992:Databases as Topic; D004194:Disease; D004347:Drug Interactions; D058492:Drug Repositioning; D005786:Gene Expression Regulation; D006801:Humans; D060066:Protein Interaction Maps; D011506:Proteins / Q000378:metabolism; D015203:Reproducibility of Results; D012984:Software; D049490:Systems Biology / Q000379:methods*
chemical_list: D011506:Proteins
keywords: Alzheimer’s disease; DrugGenEx-NET; Gene expression analysis; Inflammatory bowel disease; Parkinson’s disease; Polypharmacology; Rheumatoid arthritis; TMFS