title: Global analysis reveals families of chemical motifs enriched for HERG inhibitors.
abstract: Promiscuous inhibition of the human ether-à-go-go-related gene (hERG) potassium channel by drugs poses a major risk for life threatening arrhythmia and costly drug withdrawals. Current knowledge of this phenomenon is derived from a limited number of known drugs and tool compounds. However, in a diverse, naïve chemical library, it remains unclear which and to what degree chemical motifs or scaffolds might be enriched for hERG inhibition. Here we report electrophysiology measurements of hERG inhibition and computational analyses of >300,000 diverse small molecules. We identify chemical 'communities' with high hERG liability, containing both canonical scaffolds and structurally distinctive molecules. These data enable the development of more effective classifiers to computationally assess hERG risk. The resultant predictive models now accurately classify naïve compound libraries for tendency of hERG inhibition. Together these results provide a more complete reference map of characteristic chemical motifs for hERG liability and advance a systematic approach to rank chemical collections for cardiotoxicity risk.
authors.affiliation: The Solomon H. Snyder Department of Neuroscience, High Throughput Biology Center and Johns Hopkins Ion Channel Center (JHICC), Johns Hopkins University, 733 North Broadway, Baltimore, MD 21205, United States of America.
authors.forename: Fang
authors.initials: F
authors.lastname: Du
authors.affiliation: The Solomon H. Snyder Department of Neuroscience, High Throughput Biology Center and Johns Hopkins Ion Channel Center (JHICC), Johns Hopkins University, 733 North Broadway, Baltimore, MD 21205, United States of America.
authors.forename: Joseph J
authors.initials: JJ
authors.lastname: Babcock
authors.affiliation: The Solomon H. Snyder Department of Neuroscience, High Throughput Biology Center and Johns Hopkins Ion Channel Center (JHICC), Johns Hopkins University, 733 North Broadway, Baltimore, MD 21205, United States of America.
authors.forename: Haibo
authors.initials: H
authors.lastname: Yu
authors.affiliation: The Solomon H. Snyder Department of Neuroscience, High Throughput Biology Center and Johns Hopkins Ion Channel Center (JHICC), Johns Hopkins University, 733 North Broadway, Baltimore, MD 21205, United States of America.
authors.forename: Beiyan
authors.initials: B
authors.lastname: Zou
authors.affiliation: The Solomon H. Snyder Department of Neuroscience, High Throughput Biology Center and Johns Hopkins Ion Channel Center (JHICC), Johns Hopkins University, 733 North Broadway, Baltimore, MD 21205, United States of America.
authors.forename: Min
authors.initials: M
authors.lastname: Li
mesh_terms: D000818:Animals; D016466:CHO Cells; D066126:Cardiotoxicity; D006224:Cricetinae; D003412:Cricetulus; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D026902:Potassium Channel Blockers / Q000009:adverse effects / Q000737:chemistry* / Q000494:pharmacology; D011485:Protein Binding; D054852:Small Molecule Libraries / Q000009:adverse effects / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; D026902:Potassium Channel Blockers; D054852:Small Molecule Libraries