A Novel Drug-Mouse Phenotypic Similarity Method Detects Molecular Determinants of Drug Effects
| Autor: | Ingo Vogt, Jeanette Prinz, Monica Campillos, Gianluca Adornetto |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Drug Drug Research and Development media_common.quotation_subject Mouse Models Computational biology Biology Bioinformatics Research and Analysis Methods 03 medical and health sciences Cellular and Molecular Neuroscience Model Organisms Adverse Reactions Drug Therapy Drug Discovery Medicine and Health Sciences Genetics Drug Interactions Molecular Biology Gene lcsh:QH301-705.5 Ecology Evolution Behavior and Systematics media_common Pharmacology Ecology Drug discovery Pharmaceutics Drug Information In vitro toxicology Prokineticin receptor 2 Biology and Life Sciences Phenotypic trait Animal Models Phenotype Phenotypes 030104 developmental biology Computational Theory and Mathematics lcsh:Biology (General) Pharmacogenetics Modeling and Simulation Research Article |
| Zdroj: | PLoS Computational Biology, Vol 12, Iss 9, p e1005111 (2016) PLoS Computational Biology PLoS Comput. Biol. 12, DOI: 10.1371/journal.pcbi.1005111 (2016) |
| ISSN: | 1553-7358 |
| DOI: | 10.1371/journal.pcbi.1005111 |
| Popis: | 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. Author Summary 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. Side effects offer insight into drug action, as for example similar side effects of unrelated drugs can be caused by their common off-targets. Moreover, the phenotypes of systematic single gene perturbation screenings in mice strongly contribute to the comprehension of gene function. Here, we present a novel approach that detects molecular interactions of drugs based on the phenotypic similarity of drugs and mouse models. The method is benchmarked with diverse data sets including drug-target interactions as well as gene-drug links of pharmacogenetic associations and validated by in vitro assays. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|