Network, Transcriptomic and Genomic Features Differentiate Genes Relevant for Drug Response

Abstract

Understanding the mechanisms underlying drug therapeutic action and toxicity is crucial for the prevention and management of drug adverse reactions, and paves the way for a more efficient and rational drug design. The characterization of drug targets, drug metabolism proteins, and proteins associated to side effects according to their expression patterns, their tolerance to genomic variation and their role in cellular networks, is a necessary step in this direction. In this contribution, we hypothesize that different classes of proteins involved in the therapeutic effect of drugs and in their adverse effects have distinctive transcriptomics, genomics and network features. We explored the properties of these proteins within global and organ-specific interactomes, using multi-scale network features, evaluated their gene expression profiles in different organs and tissues, and assessed their tolerance to loss-of-function variants leveraging data from 60K subjects. We found that drug targets that mediate side effects are more central in cellular networks, more intolerant to loss-of-function variation, and show a wider breadth of tissue expression than targets not mediating side effects. In contrast, drug metabolizing enzymes and transporters are less central in the interactome, more tolerant to deleterious variants, and are more constrained in their tissue expression pattern. Our findings highlight distinctive features of proteins related to drug action, which could be applied to prioritize drugs with fewer probabilities of causing side effects.

Exploration of the DARTable Genome- a Resource Enabling Data-Driven NAMs for Developmental and Reproductive Toxicity Prediction

“…Conversely, proteins that are not part of HDG are characterized by lower degree and their role is associated to their own modules in the network. Similar findings were observed in the previous study ( Piñero et al, 2018 ) for Proteins Associated to Drug Toxicity. This suggests that DARTable genes appear to be coordinators and regulators of biological processes and could connect different modules within the network which would be key characteristics of transcription factors and cell signaling.…”

Transcriptional sex and regional differences in paired human atrial and ventricular cardiac biopsies collected in vivo

“…The gene expression pattern in a specific tissue is highly influenced by a number of factors that either in isolation, or in combination, may have large effects on the transcription of genes. With the application of global transcriptional analysis, essential functional mechanisms in e.g., drug response or toxicity, may be revealed (16,21,29). We have previously carried out global transcriptional profiling on paired atrial and ventricular biopsies from five male patients who underwent cardiac surgery (4).…”

Embracing the Dark Side: Computational Approaches to Unveil the Functionality of Genes Lacking Biological Annotation in Drug-Induced Liver Injury

“…In the context of drug development, PINs have been employed to understand the perturbations elicited by drug treatment in cellular processes, and to characterize drug targets ( Yıldırım et al, 2007 ) and side effects ( Wang et al, 2013 ). Recently, Piñero et al (2018) has shown that within the set of drug targets, those that are related to side effects are more central in the interactome at local, global and meso-scale level. In the current study, we have used interactome data to highlight genes with strong molecular data, such as genes LRBA , which showed over 400 interaction partners in BIANA database, being associated to several diseases and involved in the response to DNA damage ( Matsuoka et al, 2007 ).…”