Drug Off-Target Effects Predicted Using Structural Analysis in the Context of a Metabolic Network Model

Roger L. Chang, Li Xie, Lei Xie, Philip E. Bourne, Bernhard Ø. Palsson, Roland L. Dunbrack
2010 PLoS Computational Biology  
Recent advances in structural bioinformatics have enabled the prediction of protein-drug off-targets based on their ligand binding sites. Concurrent developments in systems biology allow for prediction of the functional effects of system perturbations using large-scale network models. Integration of these two capabilities provides a framework for evaluating metabolic drug response phenotypes in silico. This combined approach was applied to investigate the hypertensive side effect of the
more » ... ryl ester transfer protein inhibitor torcetrapib in the context of human renal function. A metabolic kidney model was generated in which to simulate drug treatment. Causal drug off-targets were predicted that have previously been observed to impact renal function in gene-deficient patients and may play a role in the adverse side effects observed in clinical trials. Genetic risk factors for drug treatment were also predicted that correspond to both characterized and unknown renal metabolic disorders as well as cryptic genetic deficiencies that are not expected to exhibit a renal disorder phenotype except under drug treatment. This study represents a novel integration of structural and systems biology and a first step towards computational systems medicine. The methodology introduced herein has important implications for drug development and personalized medicine.
doi:10.1371/journal.pcbi.1000938 pmid:20957118 pmcid:PMC2950675 fatcat:lq7tck57yvhfzke5k23vlmcwxi