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. 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.
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.
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Acknowledgements
This work was supported by the grant from the National Institutes of Health of USA (U54 MH084691) (to Min LI), and National Natural Science Foundation of China (Grant 81470163 and 81503056) (to Hai-bo YU).
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Supplementary Tables are available at Acta Pharmacologica Sinica's website.
Supplementary information
Supplementary Information, Table S1
The well-characterized hERG inhibitors were validated by automated patch clamp-IonWorks Quattro™. (DOC 77 kb)
Supplementary Information, Table S2
Reported hERG inhibitors were validated by automated patch clamp-IonWorks Quattro™ (DOC 529 kb)
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Yu, Hb., Zou, By., Wang, Xl. et al. Investigation of miscellaneous hERG inhibition in large diverse compound collection using automated patch-clamp assay. Acta Pharmacol Sin 37, 111–123 (2016). https://doi.org/10.1038/aps.2015.143
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DOI: https://doi.org/10.1038/aps.2015.143
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