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

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Nefazodone was used widely as an antidepressant until it was withdrawn from the U.S. market in 2004 due to hepatotoxicity.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 Small molecules, including withdrawn drugs, were evaluated using a patch-clamp method to establish a database of hERG inhibition.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 IC{sub 50} of 45.3 nM 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 π–π interactions, while an aminemore » interacted with the S624 residue in the pore region. In conclusion, Y652 and F656 in the S6 domain play critical roles in nefazodone binding. - Highlights: • Nefazodone inhibits hERG channels with an IC{sub 50} of 45.3 nM in HEK-293 cells. • Nefazodone blocks hERG channels by binding to the open channels. • Y652 and F656 are important for binding of nefazodone. • The aromatic rings of nefazodone interact with Y652 and F656 via π–π interactions.« less

Authors:
;  [1];  [2]; ; ; ;  [1];  [3];  [2]
  1. Drug Discovery Platform Technology Research Group, Korea Research Institute of Chemical Technology, Daejeon (Korea, Republic of)
  2. Korea Institute of Toxicology, Korea Research Institute of Chemical Technology, Daejeon (Korea, Republic of)
  3. College of Veterinary Medicine, Kyungpook National University, Daegu (Korea, Republic of)
Publication Date:
OSTI Identifier:
22285588
Resource Type:
Journal Article
Journal Name:
Toxicology and Applied Pharmacology
Additional Journal Information:
Journal Volume: 274; Journal Issue: 3; Other Information: Copyright (c) 2013 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA); Journal ID: ISSN 0041-008X
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; ALANINES; AMINES; CONCENTRATION RATIO; DRUGS; MUTANTS; STEREOCHEMISTRY; TOXICITY

Citation Formats

Shin, Dae-Seop, Park, Myoung Joo, Lee, Hyang-Ae, Lee, Joo Yun, Chung, Hee-Chung, Yoo, Dae Seok, Chae, Chong Hak, Park, Sang-Joon, Kim, Ki-Suk, and Bae, Myung Ae, E-mail: mbae@krict.re.kr. A novel assessment of nefazodone-induced hERG inhibition by electrophysiological and stereochemical method. United States: N. p., 2014. Web. doi:10.1016/J.TAAP.2013.12.012.
Shin, Dae-Seop, Park, Myoung Joo, Lee, Hyang-Ae, Lee, Joo Yun, Chung, Hee-Chung, Yoo, Dae Seok, Chae, Chong Hak, Park, Sang-Joon, Kim, Ki-Suk, & Bae, Myung Ae, E-mail: mbae@krict.re.kr. A novel assessment of nefazodone-induced hERG inhibition by electrophysiological and stereochemical method. United States. https://doi.org/10.1016/J.TAAP.2013.12.012
Shin, Dae-Seop, Park, Myoung Joo, Lee, Hyang-Ae, Lee, Joo Yun, Chung, Hee-Chung, Yoo, Dae Seok, Chae, Chong Hak, Park, Sang-Joon, Kim, Ki-Suk, and Bae, Myung Ae, E-mail: mbae@krict.re.kr. 2014. "A novel assessment of nefazodone-induced hERG inhibition by electrophysiological and stereochemical method". United States. https://doi.org/10.1016/J.TAAP.2013.12.012.
@article{osti_22285588,
title = {A novel assessment of nefazodone-induced hERG inhibition by electrophysiological and stereochemical method},
author = {Shin, Dae-Seop and Park, Myoung Joo and Lee, Hyang-Ae and Lee, Joo Yun and Chung, Hee-Chung and Yoo, Dae Seok and Chae, Chong Hak and Park, Sang-Joon and Kim, Ki-Suk and Bae, Myung Ae, E-mail: mbae@krict.re.kr},
abstractNote = {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 IC{sub 50} of 45.3 nM 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 π–π 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. - Highlights: • Nefazodone inhibits hERG channels with an IC{sub 50} of 45.3 nM in HEK-293 cells. • Nefazodone blocks hERG channels by binding to the open channels. • Y652 and F656 are important for binding of nefazodone. • The aromatic rings of nefazodone interact with Y652 and F656 via π–π interactions.},
doi = {10.1016/J.TAAP.2013.12.012},
url = {https://www.osti.gov/biblio/22285588}, journal = {Toxicology and Applied Pharmacology},
issn = {0041-008X},
number = 3,
volume = 274,
place = {United States},
year = {Sat Feb 01 00:00:00 EST 2014},
month = {Sat Feb 01 00:00:00 EST 2014}
}