Predicting drug-target interactions through integrative analysis of chemogenetic assays in yeast

Chemical-genomic and genetic interaction profiling approaches are widely used to study mechanisms of drug action and resistance. However, there exist a number of scoring algorithms customized to different experimental assays, the relative performance of which remains poorly understood, especially with respect to different types of chemogenetic assays. Using yeast Saccharomyces cerevisiae as a test bed, we carried out a systematic evaluation among the main drug target analysis approaches in terms of predicting global drug-target interaction networks. We found drastic differences in their performance across different chemical-genomic assay types, such as those based on heterozygous and homozygous diploid or haploid deletion mutant libraries. Moreover, a relatively small overlap in the predicted targets was observed between those approaches that use either chemical-genomic screening alone or combined with genetic interaction profiling. A rank-based integration of the complementary scoring approaches led to improved overall performance, demonstrating that genetic interaction profiling provides added information on drug target prediction. Optimal performance was achieved when focusing specifically on the negative tail of the genetic interactions, suggesting that combining synthetic lethal interactions with chemical-genetic interactions provides highest information on drug-target interactions. A network view of rapamycin-interacting genes, pathways and complexes was used as an example to demonstrate the benefits of such integrated and optimized analysis of chemogenetic assays in yeast.