Predicting Drug Synergy and Antagonism from Genetic Interaction Neighborhoods

Abstract

Although drug combinations have proven efficacious in a variety of diseases, the design of such regimens often involves extensive experimental screening due to the myriad choice of drugs and doses. To address these challenges, we utilize the budding yeast Saccharomyces cerevisiae as a model organism to evaluate whether drug synergy or antagonism is mediated through genetic interactions between their target genes. Specifically, we hypothesize that if the inhibition targets of one chemical compound are in close proximity to those of a second compound in a genetic interaction network, then the compound pair will exhibit synergy or antagonism. Graph metrics are employed to make precise the notion of proximity in a network. Knowledge of genetic interactions and small-molecule targets are compiled through literature sources and curated databases, with predictions validated according to experimentally determined gold standards. Finally, we test whether genetic interactions propagate through networks according to a \"guilt-by-association\" framework. Our results suggest that close proximity between the target genes of one drug and those of another drug does not strongly predict synergy or antagonism. In addition, we find that the extent to which the growth of a double gene mutant deviates from expectation is moderately anti-correlated with their distance in a genetic interaction network.