Stereoselective Block of hERG Channel by Bupivacaine Scrutinized at Molecular Level

Authors: Grilo, Liliana Sintra¹; Carrupt, Pierre-Alain²; Daina, Antoine²

Source: CHIMIA International Journal for Chemistry, Volume 64, Number 3, March 2010 , pp. 165-169(5)

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Abstract:

In the heart, the hERG voltage-gated potassium channel mediates the I_Kr current, which is crucial for the duration of cardiac action potential. Undesired block of the channel may prolong the QT interval with increased risk of malignant ventricular arrhythmia called torsades de pointes. Although the molecular determinants of hERG block are intensively studied, stereoselectivity has been poorly investigated. Levo-(S)-bupivacaine was the first drug reported to have higher affinity for hERG than its enantiomer. This study aims at understanding the principles underlying the stereoselectivity of bupivacaine block with the help of molecular modeling. Putative binding modes of levo-(S)- and dextro-(R)-bupivacaine inside an open form model of hERG channel were predicted by docking simulations, allowing a clear depiction of ligand-protein interactions. Estimated binding energies for both enantiomers to wild-type channel are in line with previously published electrophysiology measurements. These results may be considered as a confirmation at the molecular level of bupivacaine stereoselective binding towards hERG. Moreover this information lays the foundations for a structural guideline to filter out potentially cardiotoxic drug candidates in silico.

Keywords: BUPIVACAINE; CARDIOTOXICITY; DOCKING; HERG-BLOCK; STEREOSELECTIVITY

Document Type: Research article

DOI: http://dx.doi.org/10.2533/chimia.2010.165

Affiliations: 1: School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, 30, Quai Ernest-Ansermet, CH-1211 Geneva 4; Department of Clinical Research, University of Bern, Murtenstrasse 35, CH-3010 Bern 2: School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, 30, Quai Ernest-Ansermet, CH-1211 Geneva 4

Publication date: 2010-03-01

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International Journal for Chemistry and Official Membership Journal of the Swiss Chemical Society (SCS) and its Divisions

CHIMIA, a scientific journal for chemistry in the broadest sense, is published 10 times a year and covers the interests of a wide and diverse readership. Contributions from all fields of chemistry and related areas are considered for publication in the form of Review Articles and Notes. A characteristic feature of CHIMIA are the thematic issues, each devoted to an area of great current significance.
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Stereoselective Block of hERG Channel by Bupivacaine Scrutinized at Molecular Level

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