Title
A Systems Biology Strategy for Predicting Similarities and Differences of Drug Effects: Evidence for Drug-specific Modulation of Inflammation in Atherosclerosis
Author
Kleemann, R.
Bureeva, S.
Perlina, A.
Kaput, J.
Verschuren, L.
Wielinga, P.Y.
Hurt-Camejo, E.
Nikolsky, Y.
van Ommen, B.
Kooistra, T.
Publication year
2011
Abstract
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, IFN?, TGFß, IL1ß, TNFa, LPS), transcriptional regulators (NF?B, C/EBP, STAT3, AP-1) and enzymes (PKCd, 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. © 2011 Kleemann et al; licensee BioMed Central Ltd.
Subject
Life
MHR - Metabolic Health Research PHS - Pharmacokinetics & Human Studies
EELS - Earth, Environmental and Life Sciences
Health Pharmacology
Trifluoro
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http://resolver.tudelft.nl/uuid:3d521ab2-8254-48f9-9c53-ab2da0b38e06
DOI
https://doi.org/10.1186/1752-0509-5-125
TNO identifier
436038
ISSN
1752-0509
Source
BMC Systems Biology, 5
Article number
No.: 125
Document type
article