Linked Life Data

21624711

Source:http://linkedlifedata.com/resource/pubmed/id/21624711

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
8
pubmed:dateCreated
2011-6-13
pubmed:abstractText
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.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Aug
pubmed:issn
1768-3254
pubmed:author
pubmed:copyrightInfo
Copyright © 2011 Elsevier Masson SAS. All rights reserved.
pubmed:issnType
Electronic
pubmed:volume
46
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
3486-98
pubmed:meshHeading
pubmed-meshheading:21624711-Action Potentials, pubmed-meshheading:21624711-Anesthetics, Local, pubmed-meshheading:21624711-Anti-Allergic Agents, pubmed-meshheading:21624711-Arrhythmias, Cardiac, pubmed-meshheading:21624711-Binding Sites, pubmed-meshheading:21624711-Bupivacaine, pubmed-meshheading:21624711-Ether-A-Go-Go Potassium Channels, pubmed-meshheading:21624711-HEK293 Cells, pubmed-meshheading:21624711-Heart, pubmed-meshheading:21624711-Humans, pubmed-meshheading:21624711-Molecular Dynamics Simulation, pubmed-meshheading:21624711-Mutation, pubmed-meshheading:21624711-Plasmids, pubmed-meshheading:21624711-Potassium Channel Blockers, pubmed-meshheading:21624711-Protein Binding, pubmed-meshheading:21624711-Recombinant Proteins, pubmed-meshheading:21624711-Stereoisomerism, pubmed-meshheading:21624711-Terfenadine, pubmed-meshheading:21624711-Thermodynamics, pubmed-meshheading:21624711-Transfection
pubmed:year
2011
pubmed:articleTitle
Block of the hERG channel by bupivacaine: Electrophysiological and modeling insights towards stereochemical optimization.
pubmed:affiliation
School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, Quai Ernest-Ansermet 30, 1211 Geneva 4, Switzerland.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't