Computer Simulations Reveal a Novel Blocking Mode of the hERG Ion Channel by the Antiarrhythmic Agent Clofilium

Molecular Informatics
Daniel Șterbuleac, Călin Lucian Maniu

Abstract

The binding modes of many hERG ion channel blockers are well understood, but a notable exception is clofilium, a potent antiarrhythmic agent whose action relies on blocking the current mediated by hERG. From the previously hypothesized binding modes of clofilium to hERG, only two can explain most of the experimental results. In this study, computer simulations are performed in order to analyze the hypothesized binding modes and to identify the consensus one. This is accomplished by employing molecular dynamics (MD) simulations and interaction energy calculations. The results show an unexpected binding mode, in which the quaternary nitrogen is placed in the upper part of the inner cavity, interacting strongly with Ser624, while the chlorophenyl group is located in the lower part, in better agreement with previous experimental results. This novel binding position also explains the higher affinity of clofilium for the related hEag1 channel and was correlated with the possibility that potent hERG blockers interact in specific ways with the residues near the intracellular activation gate, offering a new explanation that could help predict the potency of other hERG-blocking compounds.

References

Feb 1, 1996·Journal of Molecular Graphics·W HumphreyK Schulten
Apr 29, 2000·Nature·J Aqvist, V Luzhkov
Sep 27, 2000·Proceedings of the National Academy of Sciences of the United States of America·J S MitchesonM C Sanguinetti
Jul 17, 2001·Molecular Pharmacology·K KamiyaM C Sanguinetti
Feb 28, 2002·The Journal of Biological Chemistry·Martin Tristani-FirouziMichael C Sanguinetti
Jan 11, 2003·British Journal of Pharmacology·Guido Gessner, Stefan H Heinemann
Dec 31, 2003·The Journal of Biological Chemistry·David FernandezMichael C Sanguinetti
Apr 23, 2004·Molecular Pharmacology·Guido GessnerStefan H Heinemann
Jul 21, 2004·Journal of Computational Chemistry·Eric F PettersenThomas E Ferrin
Jul 22, 2004·Molecular Pharmacology·Matthew PerryJohn Mitcheson
Aug 17, 2004·Molecular Pharmacology·Harry J WitchelJohn S Mitcheson
Jan 26, 2005·Journal of Chemical Information and Modeling·John J Irwin, Brian K Shoichet
Oct 14, 2005·Journal of Computational Chemistry·James C PhillipsKlaus Schulten
Jan 18, 2006·Bioorganic & Medicinal Chemistry·Ramy FaridRobert A Pearlstein
Feb 14, 2006·Molecular Pharmacology·Kaichiro KamiyaMichael C Sanguinetti
Oct 11, 2007·Journal of Computational Chemistry·Matteo MasettiMaurizio Recanatini
Oct 29, 2008·The Journal of General Physiology·Sarah L Wynia-SmithGail A Robertson
Nov 7, 2008·Journal of Pharmacological Sciences·Kaichiro KamiyaMichael C Sanguinetti
Jul 21, 2010·The Journal of Physiology·Matthew PerryJohn Mitcheson
Oct 4, 2011·Journal of Structural Biology·Zheng YangThomas E Ferrin
Jul 9, 2013·Journal of Computational Chemistry·Jing Huang, Alexander D MacKerell
May 9, 2014·Current Topics in Medicinal Chemistry·Rodolpho C BragaCarolina H Andrade
Dec 1, 2004·Drug Discovery Today. Technologies·Maurizio RecanatiniAndrea Cavalli
Apr 10, 2015·Molecular Pharmacology·Wei WuMichael C Sanguinetti
Jun 5, 2015·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·María Jesús García-GodoyAntonio J Nebroand José F Aldana-Montes
Apr 14, 2016·Scientific Reports·P SaxenaA Stary-Weinzinger
Jun 21, 2016·Current Protocols in Bioinformatics·Benjamin Webb, Andrej Sali
Aug 23, 2016·Bioorganic & Medicinal Chemistry·Martin KotevModesto Orozco
Oct 27, 2016·Journal of Computer-aided Molecular Design·Remigijus Didziapetris, Kiril Lanevskij
Jan 23, 2017·Biochemical and Biophysical Research Communications·Harald BernsteinerAnna Stary-Weinzinger
Apr 18, 2017·Current Topics in Medicinal Chemistry·Soren WackerLaura L Perissinotti
Apr 22, 2017·Cell·Weiwei Wang, Roderick MacKinnon
May 16, 2017·Frontiers in Chemistry·Giulia ChemiMargherita Brindisi
Nov 21, 2017·Journal of Molecular Graphics & Modelling·Busecan AksoydanSerdar Durdagi

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Citations

Aug 28, 2021·International Journal of Molecular Sciences·Žan ToplakTihomir Tomašič

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