Drug binding to the inactivated state is necessary but not sufficient for high-affinity binding to human ether-a-go-go-related gene channels.

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Perrin MJ, Kuchel PW, Campbell TJ, Vandenberg JI

Drug binding to the inactivated state is necessary but not sufficient for high-affinity binding to human ether-a-go-go-related gene channels.

Mol Pharmacol. 2008 Nov;74(5):1443-52. doi: 10.1124/mol.108.049056. Epub 2008 Aug 13.

PubMed ID

18701618 [ View in PubMed

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Abstract

Drug block of the human ether-a-go-go-related gene K(+) channel (hERG) is the most common cause of acquired long QT syndrome, a disorder of cardiac repolarization that may result in ventricular tachycardia and sudden cardiac death. We investigated the open versus inactivated state dependence of drug block by using hERG mutants N588K and N588E, which shift the voltage dependence of inactivation compared with wild-type but in which the mutated residue is remote from the drug-binding pocket in the channel pore. Four high-affinity drugs (cisapride, dofetilide, terfenadine, and astemizole) demonstrated lower affinity for the inactivation-deficient N588K mutant hERG channel compared with N588E and wild-type hERG. Three of four low-affinity drugs (erythromycin, perhexiline, and quinidine) demonstrated no preference for N588E over N588K channels, whereas dl-sotalol was an example of a low-affinity state-dependent blocker. All five state-dependent blockers showed an even lower affinity for S620T mutant hERG (no inactivation) compared with N588K mutant hERG (greatly reduced inactivation). Computer modeling indicates that the reduced affinity for S620T compared with N588K and wild-type channels can be explained by the relative kinetics of drug block and unblock compared with the kinetics of inactivation and recovery from inactivation. We were also able to calculate, for the first time, the relative affinities for the inactivated versus the open state, which for the drugs tested here ranged from 4- to 70-fold. Our results show that preferential binding to the inactivated state is necessary but not sufficient for high-affinity binding to hERG channels.

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Perhexiline	Potassium voltage-gated channel subfamily H member 2	Protein	Humans	Unknown	Not Available	Details