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Block of the hERG channel by bupivacaine: Electrophysiological and modeling insights towards stereochemical optimization.

Type of publication Peer-reviewed
Publikationsform Original article (peer-reviewed)
Publication date 2011
Author Sintra Grilo Liliana, Carrupt Pierre-Alain, Abriel Hugues, Daina Antoine,
Project In vivo relevance of the PY and PDZ-domain binding motifs of the cardiac sodium channel Nav1.5
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Original article (peer-reviewed)

Journal European journal of medicinal chemistry
Volume (Issue) 46(8)
Page(s) 3486 - 98
Title of proceedings European journal of medicinal chemistry
DOI 10.1016/j.ejmech.2011.05.015


The hERG voltage-gated potassium channel mediates the cardiac I(Kr) current, which is crucial for the duration of the cardiac action potential. Undesired block of the channel by certain drugs may prolong the QT interval and increase the risk of malignant ventricular arrhythmias. Although the molecular determinants of hERG block have been intensively studied, not much is known about its stereoselectivity. Levo-(S)-bupivacaine was the first drug reported to have a higher affinity to block hERG than its enantiomer. This study strives to understand the principles underlying the stereoselectivity of bupivacaine block with the help of mutagenesis analyses and molecular modeling simulations. Electrophysiological measurements of mutated hERG channels allowed for the identification of residues involved in bupivacaine binding and stereoselectivity. Docking and molecular mechanics simulations for both enantiomers of bupivacaine and terfenadine (a non-stereoselective blocker) were performed inside an open-state model of the hERG channel. The predicted binding modes enabled a clear depiction of ligand-protein interactions. Estimated binding affinities for both enantiomers were consistent with electrophysiological measurements. A similar computational procedure was applied to bupivacaine enantiomers towards two mutated hERG channels (Tyr652Ala and Phe656Ala). This study confirmed, at the molecular level, that bupivacaine stereoselectively binds the hERG channel. These results help to lay the foundation for structural guidelines to optimize the cardiotoxic profile of drug candidates in silico.