Drug discovery using chemical systems biology: identification of the protein-ligand binding network to explain the side effects of CETP inhibitors.
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that one CETP inhibitor, Torcetrapib, has deadly off-target effects as a result of hypertension, and hence it has been withdrawn from phase III clinical trials.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.
Xie
Li
L
Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, California, USA. lxie@sdsc.edu
Li
Jerry
J
Xie
Lei
L
Bourne
Philip E
PE
D000924:Anticholesteremic Agents / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D053480:Cholesterol Ester Transfer Proteins / Q000037:antagonists & inhibitors*; D016000:Cluster Analysis; D030541:Databases, Genetic; D055808:Drug Discovery / Q000379:methods*; D053263:Gene Regulatory Networks / Q000187:drug effects; D007249:Inflammation; D008024:Ligands; D008954:Models, Biological; D015233:Models, Statistical; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D020543:Proteome; D018160:Receptors, Cytoplasmic and Nuclear / Q000187:drug effects; D012084:Renin-Angiotensin System / Q000187:drug effects; D049490:Systems Biology / Q000379:methods*
D000924:Anticholesteremic Agents; C506642:CETP protein, human; D053480:Cholesterol Ester Transfer Proteins; D008024:Ligands; D020543:Proteome; D018160:Receptors, Cytoplasmic and Nuclear