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PLoS One. 2013 Jul 23;8(7):e69513. doi: 10.1371/journal.pone.0069513. Print 2013.

Integrated analysis of drug-induced gene expression profiles predicts novel hERG inhibitors.

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1
The Solomon H. Snyder Department of Neuroscience and High Throughput Biology Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.

Abstract

Growing evidence suggests that drugs interact with diverse molecular targets mediating both therapeutic and toxic effects. Prediction of these complex interactions from chemical structures alone remains challenging, as compounds with different structures may possess similar toxicity profiles. In contrast, predictions based on systems-level measurements of drug effect may reveal pharmacologic similarities not evident from structure or known therapeutic indications. Here we utilized drug-induced transcriptional responses in the Connectivity Map (CMap) to discover such similarities among diverse antagonists of the human ether-à-go-go related (hERG) potassium channel, a common target of promiscuous inhibition by small molecules. Analysis of transcriptional profiles generated in three independent cell lines revealed clusters enriched for hERG inhibitors annotated using a database of experimental measurements (hERGcentral) and clinical indications. As a validation, we experimentally identified novel hERG inhibitors among the unannotated drugs in these enriched clusters, suggesting transcriptional responses may serve as predictive surrogates of cardiotoxicity complementing existing functional assays.

PMID:
23936032
PMCID:
PMC3720659
DOI:
10.1371/journal.pone.0069513
[Indexed for MEDLINE]
Free PMC Article
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