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2016 ; 17
(1
): 202
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DrugGenEx-Net: a novel computational platform for systems pharmacology and gene
expression-based drug repurposing
#MMPMID27151405
Issa NT
; Kruger J
; Wathieu H
; Raja R
; Byers SW
; Dakshanamurthy S
BMC Bioinformatics
2016[May]; 17
(1
): 202
PMID27151405
show ga
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.