Docking model of drug binding to the human ether-a-go-go potassium channel guided by tandem dimer mutant patch-clamp data: a synergic approach.
Article Details
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Imai YN, Ryu S, Oiki S
Docking model of drug binding to the human ether-a-go-go potassium channel guided by tandem dimer mutant patch-clamp data: a synergic approach.
J Med Chem. 2009 Mar 26;52(6):1630-8. doi: 10.1021/jm801236n.
- PubMed ID
- 19260734 [ View in PubMed]
- Abstract
To characterize drug binding to the human ether-a-go-go related gene (hERG) channel, a synergic approach interplaying patch-clamp experiments and a docking study was developed. Mutations were introduced into concatenated dimers of the hERG channel that were assembled into a heterotetramer with mutated diagonal subunits. The binding affinities of three drugs (cisapride, terfenadine, and N-[4-[[1-[2-(6-methyl-2-pyridinyl)ethyl]-4-piperidinyl]carbonyl]phenyl]methanesul fonamide dihydrochloride (E-4031, 1)) to a set of mutant channels were examined electrophysiologically to assess the involved residues, their number, and relative positions. Cisapride and 1 interacted with Tyr652 residues on adjacent subunits, while terfenadine interacted with Tyr652 residues on diagonal, but not on adjacent, subunits. Phe656 was involved in the binding of all three drugs, and Ser624 was found to be only involved in cisapride and 1. The docking models demonstrated that pi-pi and CH-pi interactions rather than cation-pi interaction play a key role in drug binding to the hERG channel.
DrugBank Data that Cites this Article
- Binding Properties
Drug Target Property Measurement pH Temperature (°C) Cisapride Potassium voltage-gated channel subfamily H member 2 IC 50 (nM) 10 N/A N/A Details Terfenadine Potassium voltage-gated channel subfamily H member 2 IC 50 (nM) 30 N/A N/A Details