Drug Off-Target Effects Predicted Using Structural Analysis in the Context of a Metabolic Network Model
First, the human proteome was screened to identify off-target drug-binding sites. The resulting list of putative off-targets was filtered to focus on just metabolic proteins. Then, for each predicted metabolic off-target, the endogenous functional sites were compared to the predicted drug-binding site to identify overlap. Off-target proteins for which overlapping binding sites were identified were considered to be competitively inhibitable by the drug at the overlapping endogenous functional sites. The functional consequences of such inhibitions were then tested in an appropriate context-specific metabolic model. All possible individual gene knockouts were also simulated to predict genetic disorders that lead to functional deficiencies either alone or in combination with drug treatment. Those off-targets whose inhibition impacted model function represent causal off-targets predicted to be associated with the drug response phenotype, and the gene knockouts that impacted model function represent genetic risk factors for metabolic disorders, which may lead to amplification of the drug response phenotype.