Drug Binding Interactions in the Inner Cavity of hERG Channels: Molecular Insights from Structure-Activity Relationships of Clofilium and Ibutilide Analogs
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...
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Published in | Molecular pharmacology Vol. 69; no. 2; pp. 509 - 519 |
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Main Authors | , , , , , , , |
Format | Journal Article |
Language | English |
Published |
United States
American Society for Pharmacology and Experimental Therapeutics
01.02.2006
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Subjects | |
Online Access | Get full text |
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Summary: | 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 IC 50 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. |
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ISSN: | 0026-895X 1521-0111 |
DOI: | 10.1124/mol.105.016741 |