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Pharmacophore modeling for hERG channel facilitation
Yuko Yamakawa1, Kazuharu Furutani, Atsushi Inanobe
1Department of Pharmacology, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan.
Biochemical and Biophysical Research Communications
|January 17, 2012
Summary
Facilitation, an enhancement of human ether-a-go-go-related gene (hERG) channel activity, is common among hERG channel blockers. A new pharmacophore model reveals distinct structural properties responsible for this facilitation effect, separate from channel block.
Area of Science:
- Pharmacology
- Molecular Biology
- Cardiovascular Science
Background:
- Human ether-a-go-go-related gene (hERG) channels are crucial for cardiac repolarization.
- Unintended hERG channel block can lead to cardiac arrhythmias.
- Some compounds exhibit 'facilitation,' enhancing channel activity post-depolarization.
Purpose of the Study:
- To identify structural properties of compounds that induce hERG channel facilitation.
- To develop a pharmacophore model for hERG channel facilitation.
Main Methods:
- Assayed facilitation effects of diverse hERG channel blockers in Xenopus oocytes.
- Constructed and verified a pharmacophore model for hERG channel facilitation.
- Compared pharmacophore models for facilitation and channel block.
Main Results:
- Ten of 13 tested compounds demonstrated hERG channel facilitation.
- A pharmacophore model comprising one positive and three hydrophobic features was developed.
- The spatial arrangement of features for facilitation differs from that for hERG channel block.
Conclusions:
- hERG channel facilitation is a common effect of hERG channel blockers.
- Distinct structural features and interactions mediate hERG channel block and facilitation.
- Understanding these distinct interactions can inform drug safety and design.
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