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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.

SUBMITTER: Pinero J

PROVIDER: S-EPMC6168038 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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

Piñero Janet J Gonzalez-Perez Abel A Guney Emre E Aguirre-Plans Joaquim J Sanz Ferran F Oliva Baldo B Furlong Laura I LI

Frontiers in genetics 20180925

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 hypo ...[more]

PMID: 30319692

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

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

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