Predicting inhibitory and activatory drug targets by chemically and genetically perturbed transcriptome signatures

Genome-wide identification of all target proteins of drug candidate compounds is a challenging issue in drug discovery. Moreover, emerging phenotypic effects, including therapeutic and adverse effects, are heavily dependent on the inhibition or activation of target proteins. Here we propose a novel computational method for predicting inhibitory and activatory targets of drug candidate compounds. Specifically, we integrated chemically-induced and genetically-perturbed gene expression profiles in human cell lines, which avoided dependence on chemical structures of compounds or proteins. Predictive models for individual target proteins were simultaneously constructed by the joint learning algorithm based on transcriptomic changes in global patterns of gene expression profiles following chemical treatments, and following knock-down and over-expression of proteins. This method discriminates between inhibitory and activatory targets and enables accurate identification of therapeutic effects. Herein, we comprehensively predicted drug–target–disease association networks for 1,124 drugs, 829 target proteins, and 365 human diseases, and validated some of these predictions in vitro . The proposed method is expected to facilitate identification of new drug indications and potential adverse effects.