Compound Target Identification in Tissue-Specific Interaction Networks

Abstract

Characterizing all possible side effects of compounds is not a trivial task due to unknown off-target proteins that might eventually lead lethal reactions. There is still a tremendous need of computational methods to identify protein targets of a new compound. We have performed a comprehensive analysis for identification of protein targets by integrating tissue-specific protein-protein interaction (PPI) networks and compound induced transcriptome data. Several network centrality metrics are computed to suggest the most probable off-targets of a given compound. The effects of interaction types between proteins and tissue-specific PPI networks are evaluated from multiple perspectives. Usage of network centrality metrics on a tissue-specific PPI network enhances the correct prediction rate of known targets of a given compound. The detailed analysis of successfully identified known targets indicated that degree and local radiality metrics are more practical for determining different types of target protein families, such as GPCR, chemokines, proteasome, and protein kinase families. Therefore, the proposed computational pipeline is applicable while investigating proteins from these families that can be especially targeted for treatment of complex diseases. To the best of our knowledge, this study for the first time presents how tissue-specific transcriptome changes alter the topological structure of PPI networks and the relative effects of tissue-specific networks in target identification. Overall, the proposed computational methods are practical tools for choosing more accurate protein targets for later computational analysis and wet-lab experiments.