title: Investigation of miscellaneous hERG inhibition in large diverse compound collection using automated patch-clamp assay.
abstract: OBJECTIVE
  hERG potassium channels display miscellaneous interactions with diverse chemical scaffolds. In this study we assessed the hERG inhibition in a large compound library of diverse chemical entities and provided data for better understanding of the mechanisms underlying promiscuity of hERG inhibition.
  
  
  METHODS
  Approximately 300 000 compounds contained in Molecular Library Small Molecular Repository (MLSMR) library were tested. Compound profiling was conducted on hERG-CHO cells using the automated patch-clamp platform-IonWorks Quattro(™).
  
  
  RESULTS
  The compound library was tested at 1 and 10 μmol/L. IC50 values were predicted using a modified 4-parameter logistic model. Inhibitor hits were binned into three groups based on their potency: high (IC50<1 μmol/L), intermediate (1 μmol/L< IC50<10 μmol/L), and low (IC50>10 μmol/L) with hit rates of 1.64%, 9.17% and 16.63%, respectively. Six physiochemical properties of each compound were acquired and calculated using ACD software to evaluate the correlation between hERG inhibition and the properties: hERG inhibition was positively correlative to the physiochemical properties ALogP, molecular weight and RTB, and negatively correlative to TPSA.
  
  
  CONCLUSIONS
  Based on a large diverse compound collection, this study provides experimental evidence to understand the promiscuity of hERG inhibition. This study further demonstrates that hERG liability compounds tend to be more hydrophobic, high-molecular, flexible and polarizable.
authors.affiliation: State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors.forename: Hai-bo
authors.initials: HB
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, Baltimore, MD 21205, USA.|Now in Molecular Devices LLC, Sunnyvale, CA 94089, USA.
authors.forename: Bei-yan
authors.initials: BY
authors.lastname: Zou
authors.affiliation: State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors.forename: Xiao-liang
authors.initials: XL
authors.lastname: Wang
authors.affiliation: The Solomon H Snyder Department of Neuroscience, High Throughput Biology Center and Johns Hopkins Ion Channel Center (JHICC), Johns Hopkins University, Baltimore, MD 21205, USA.|Now in GlaxoSmithKline (GSK), King of Prussia, PA 19406, USA.
authors.forename: Min
authors.initials: M
authors.lastname: Li
mesh_terms: D000818:Animals; D016466:CHO Cells; D002627:Chemistry, Physical; D003412:Cricetulus; D000072237:ERG1 Potassium Channel / Q000037:antagonists & inhibitors*; D057809:HEK293 Cells; D057166:High-Throughput Screening Assays; D006801:Humans; D018408:Patch-Clamp Techniques; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000072237:ERG1 Potassium Channel; C000606913:KCNH2 protein, human; D054852:Small Molecule Libraries