A novel assessment of nefazodone-induced hERG inhibition by electrophysiological and stereochemical method.

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Shin DS, Park MJ, Lee HA, Lee JY, Chung HC, Yoo DS, Chae CH, Park SJ, Kim KS, Bae MA

A novel assessment of nefazodone-induced hERG inhibition by electrophysiological and stereochemical method.

Toxicol Appl Pharmacol. 2014 Feb 1;274(3):361-71. doi: 10.1016/j.taap.2013.12.012. Epub 2013 Dec 26.

PubMed ID

24374264 [ View in PubMed

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Abstract

Nefazodone was used widely as an antidepressant until it was withdrawn from the U.S. market in 2004 due to hepatotoxicity. We have investigated methods to predict various toxic effects of drug candidates to reduce the failure rate of drug discovery. An electrophysiological method was used to assess the cardiotoxicity of drug candidates. Small molecules, including withdrawn drugs, were evaluated using a patch-clamp method to establish a database of hERG inhibition. Nefazodone inhibited hERG channel activity in our system. However, nefazodone-induced hERG inhibition indicated only a theoretical risk of cardiotoxicity. Nefazodone inhibited the hERG channel in a concentration-dependent manner with an IC50 of 45.3nM in HEK-293 cells. Nefazodone accelerated both the recovery from inactivation and its onset. Nefazodone also accelerated steady-state inactivation, although it did not modify the voltage-dependent character. Alanine mutants of hERG S6 and pore region residues were used to identify the nefazodone-binding site on hERG. The hERG S6 point mutants Y652A and F656A largely abolished the inhibition by nefazodone. The pore region mutant S624A mildly reduced the inhibition by nefazodone but T623A had little effect. A docking study showed that the aromatic rings of nefazodone interact with Y652 and F656 via pi-pi interactions, while an amine interacted with the S624 residue in the pore region. In conclusion, Y652 and F656 in the S6 domain play critical roles in nefazodone binding.

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Nefazodone	Potassium voltage-gated channel subfamily H member 2	Protein	Humans	Unknown	Antagonist	Details