Paper Info
Title
Drug Discovery Using Chemical Systems Biology: Identification Of The Protein-Ligand Binding Network To Explain The Side Effects Of Cetp Inhibitors
Abstract
Systematic identification of protein-drug interaction networks is crucial to correlate complex modes of drug action to clinical indications. We introduce a novel computational strategy to identify protein-ligand binding profiles on a genome-wide scale and apply it to elucidating the molecular mechanisms associated with the adverse drug effects of Cholesteryl Ester Transfer Protein (CETP) inhibitors. CETP inhibitors are a new class of preventive therapies for the treatment of cardiovascular disease. However, clinical studies indicated that one CETP inhibitor, Torcetrapib, has deadly off-target effects as a result of hypertension, and hence it has been withdrawn from phase III clinical trials. We have identified a panel of off-targets for Torcetrapib and other CETP inhibitors from the human structural genome and map those targets to biological pathways via the literature. The predicted protein-ligand network is consistent with experimental results from multiple sources and reveals that the side-effect of CETP inhibitors is modulated through the combinatorial control of multiple interconnected pathways. Given that combinatorial control is a common phenomenon observed in many biological processes, our findings suggest that adverse drug effects might be minimized by fine-tuning multiple off-target interactions using single or multiple therapies. This work extends the scope of chemogenomics approaches and exemplifies the role that systems biology has in the future of drug discovery.
Year
DOI
Venue
2009
10.1371/journal.pcbi.1000387
PLOS COMPUTATIONAL BIOLOGY
DocType
Volume
Issue
Journal
5
5
ISSN
Citations 
PageRank 
1553-734X
30
2.63
References 
Authors
15
4
Name
Order
Citations
PageRank
Li Xie116921.63
Jerry Li2335.47
Lei Xie344139.48
Philip E. Bourne41995388.17