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BMC Syst Biol. 2011 Aug 12;5:125. doi: 10.1186/1752-0509-5-125.

A systems biology strategy for predicting similarities and differences of drug effects: evidence for drug-specific modulation of inflammation in atherosclerosis.

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  • 1Metabolic Health Research, TNO, Zernikedreef 9, Leiden, The Netherlands. robert.kleemann@tno.nl

Abstract

BACKGROUND:

Successful drug development has been hampered by a limited understanding of how to translate laboratory-based biological discoveries into safe and effective medicines. We have developed a generic method for predicting the effects of drugs on biological processes. Information derived from the chemical structure and experimental omics data from short-term efficacy studies are combined to predict the possible protein targets and cellular pathways affected by drugs.

RESULTS:

Validation of the method with anti-atherosclerotic compounds (fenofibrate, rosuvastatin, LXR activator T0901317) demonstrated a great conformity between the computationally predicted effects and the wet-lab biochemical effects. Comparative genome-wide pathway mapping revealed that the biological drug effects were realized largely via different pathways and mechanisms. In line with the predictions, the drugs showed differential effects on inflammatory pathways (downstream of PDGF, VEGF, IFNγ, TGFβ, IL1β, TNFα, LPS), transcriptional regulators (NFκB, C/EBP, STAT3, AP-1) and enzymes (PKCδ, AKT, PLA2), and they quenched different aspects of the inflammatory signaling cascade. Fenofibrate, the compound predicted to be most efficacious in inhibiting early processes of atherosclerosis, had the strongest effect on early lesion development.

CONCLUSION:

Our approach provides mechanistic rationales for the differential and common effects of drugs and may help to better understand the origins of drug actions and the design of combination therapies.

PMID:
21838869
[PubMed - indexed for MEDLINE]
PMCID:
PMC3163556
Free PMC Article
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