title: Block of the hERG channel by bupivacaine: Electrophysiological and modeling insights towards stereochemical optimization.
abstract: 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.
authors.affiliation: School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, Quai Ernest-Ansermet 30, 1211 Geneva 4, Switzerland.
authors.forename: Liliana
authors.initials: L
authors.lastname: Sintra Grilo
authors.forename: Pierre-Alain
authors.initials: PA
authors.lastname: Carrupt
authors.forename: Hugues
authors.initials: H
authors.lastname: Abriel
authors.forename: Antoine
authors.initials: A
authors.lastname: Daina
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000779:Anesthetics, Local / Q000009:adverse effects; D018926:Anti-Allergic Agents / Q000009:adverse effects; D001145:Arrhythmias, Cardiac / Q000378:metabolism / Q000503:physiopathology; D001665:Binding Sites; D002045:Bupivacaine / Q000009:adverse effects*; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D006321:Heart / Q000187:drug effects / Q000503:physiopathology; D006801:Humans; D056004:Molecular Dynamics Simulation; D009154:Mutation; D010957:Plasmids; D026902:Potassium Channel Blockers / Q000009:adverse effects*; D011485:Protein Binding / Q000187:drug effects*; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D013237:Stereoisomerism; D016593:Terfenadine / Q000009:adverse effects*; D013816:Thermodynamics; D014162:Transfection
chemical_list: D000779:Anesthetics, Local; D018926:Anti-Allergic Agents; D051638:Ether-A-Go-Go Potassium Channels; D026902:Potassium Channel Blockers; D011994:Recombinant Proteins; D016593:Terfenadine; D002045:Bupivacaine