Investigation of miscellaneous hERG inhibition in large diverse compound collection using automated patch-clamp assay

Hai Bo Yu, Bei Yan Zou, Xiao Liang Wang, Min Li

Research output: Contribution to journalArticle

Abstract

Aim: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. IC 50 values were predicted using a modified 4-parameter logistic model. Inhibitor hits were binned into three groups based on their potency: high (IC 50 <1 μmol/L), intermediate (1 μmol/L< IC 50 <10 μmol/L), and low (IC 50 >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.Conclusion: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.

Original languageEnglish (US)
Pages (from-to)111-123
Number of pages13
JournalActa Pharmacologica Sinica
Volume37
Issue number1
DOIs
StatePublished - Jan 1 2016

Keywords

  • MLSMR library
  • automated electrophysiology
  • cardiotoxicity
  • hERG
  • high-throughput screening

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)

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