A Novel Drug-Mouse Phenotypic Similarity Method Detects Molecular Determinants of Drug Effects.

Jeanette Prinz,Ingo Vogt,Mónica Campillos,Gianluca Adornetto,Donna K Slonim

doi:10.1371/journal.pcbi.1005111

Abstract

The molecular mechanisms that translate drug treatment into beneficial and unwanted effects are largely unknown. We present here a novel approach to detect gene-drug and gene-side effect associations based on the phenotypic similarity of drugs and single gene perturbations in mice that account for the polypharmacological property of drugs. We scored the phenotypic similarity of human side effect profiles of 1,667 small molecules and biologicals to profiles of phenotypic traits of 5,384 mouse genes. The benchmarking with known relationships revealed a strong enrichment of physical and indirect drug-target connections, causative drug target-side effect links as well as gene-drug links involved in pharmacogenetic associations among phenotypically similar gene-drug pairs. The validation by in vitro assays and the experimental verification of an unknown connection between oxandrolone and prokineticin receptor 2 reinforces the ability of this method to provide new molecular insights underlying drug treatment. Thus, this approach may aid in the proposal of novel and personalized treatments.

Highlights

A drug can modulate its targets directly or indirectly and only a small proportion of these protein targets are known [1,2,3]
In order to avoid unwanted effects of current drug interventions, it is necessary to expand the knowledge of the molecular mechanisms related to drug action
We present a novel approach that detects molecular interactions of drugs based on the phenotypic similarity of drugs and mouse models

Summary

Introduction

A drug can modulate its targets directly or indirectly (e.g. via modulation of the gene expression) and only a small proportion of these protein targets are known [1,2,3] Due to this incomplete understanding of drug mode of action, current drug treatment often suffers from unwanted effects [4]. The promiscuity of many drugs, that is the tendency of drugs to modulate multiple targets [5], hampers the anticipation of drug response and adverse effects in clinical practice. This is complicated by the genomic heterogeneity in the population, which produces a large variability of efficacy and adverse effects among patients [6]. In order to personalize medication and to improve drug efficacy as well as drug safety, it is necessary to develop novel approaches expanding the knowledge of the molecular mechanisms underlying drug treatment

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