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Molecular Pharmacology

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Research ArticleArticle

Drug Binding Interactions in the Inner Cavity of hERG Channels: Molecular Insights from Structure-Activity Relationships of Clofilium and Ibutilide Analogs

Matthew Perry, Phillip J. Stansfeld, Joanne Leaney, Claire Wood, Marcel J. de Groot, Derek Leishman, Michael J. Sutcliffe and John S. Mitcheson
Molecular Pharmacology February 2006, 69 (2) 509-519; DOI: https://doi.org/10.1124/mol.105.016741
Matthew Perry
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Phillip J. Stansfeld
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Joanne Leaney
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Claire Wood
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Marcel J. de Groot
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Derek Leishman
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Michael J. Sutcliffe
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John S. Mitcheson
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Abstract

Block of human ether-a-go-go related gene (hERG) K+ channels by otherwise useful drugs is the most common cause of long QT syndrome, a disorder of cardiac repolarization that predisposes patients to potentially fatal arrhythmias. This undesirable long QT side effect has been a major reason for the withdrawal of medications from the pharmaceutical market. Understanding the molecular basis of hERG block is therefore essential to facilitate the design of safe drugs. Binding sites for hERG blockers have been mapped within the inner cavity of the channel and include aromatic residues in the S6 helix (Tyr-652, Phe-656) and residues in the pore helix (Thr-623, Ser-624, Val-625). We used mutagenesis of these residues, combined with an investigation of hERG block by close analogs of clofilium and ibutilide, to assess how specific alterations in drug structure affected potency and binding interactions. Although changing the basic nitrogen from quaternary to tertiary accelerated the onset of block, the IC50 and kinetics for recovery from block were similar. In contrast, analogs with different para-substituents on the phenyl ring had significantly different potencies for wild-type hERG block. The highest potency was achieved with polar or electronegative para-substituents, whereas neutral para-substituents had potencies more than 100-fold lower. Results from mutagenesis and molecular modeling studies suggest that phenyl ring para-substituents influence drug interactions with Thr-623, Ser-624, and Tyr-652 and strongly affect binding affinity. Together, these findings suggest that modifying the para-substituent could be a useful strategy for reducing hERG potency and increasing the safety margin of compounds in development.

  • Received July 14, 2005.
  • Accepted November 16, 2005.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 69 (2)
Molecular Pharmacology
Vol. 69, Issue 2
1 Feb 2006
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Research ArticleArticle

Drug Binding Interactions in the Inner Cavity of hERG Channels: Molecular Insights from Structure-Activity Relationships of Clofilium and Ibutilide Analogs

Matthew Perry, Phillip J. Stansfeld, Joanne Leaney, Claire Wood, Marcel J. de Groot, Derek Leishman, Michael J. Sutcliffe and John S. Mitcheson
Molecular Pharmacology February 1, 2006, 69 (2) 509-519; DOI: https://doi.org/10.1124/mol.105.016741

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Research ArticleArticle

Drug Binding Interactions in the Inner Cavity of hERG Channels: Molecular Insights from Structure-Activity Relationships of Clofilium and Ibutilide Analogs

Matthew Perry, Phillip J. Stansfeld, Joanne Leaney, Claire Wood, Marcel J. de Groot, Derek Leishman, Michael J. Sutcliffe and John S. Mitcheson
Molecular Pharmacology February 1, 2006, 69 (2) 509-519; DOI: https://doi.org/10.1124/mol.105.016741
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