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Mechanisms and energetics of potassium channel block by local anesthetics and antifungal agents

Chen, Rong; Gryn'ova, Ganna; Wu, Yingliang; Coote, Michelle; Chung, Shin-Ho

Description

Many drug molecules inhibit the conduction of several families of cation channels by binding to a small cavity just below the selectivity filter of the channel protein. The exact mechanisms governing drug-channel binding and the subsequent inhibition of conduction are not well understood. Here the inhibition of two K+channel isoforms, Kv1.2 and KCa3.1, by two drug molecules, lidocaine and TRAM-34, is examined in atomic detail using molecular dynamics simulations. A conserved...[Show more]

dc.contributor.authorChen, Rong
dc.contributor.authorGryn'ova, Ganna
dc.contributor.authorWu, Yingliang
dc.contributor.authorCoote, Michelle
dc.contributor.authorChung, Shin-Ho
dc.date.accessioned2015-12-10T23:11:22Z
dc.identifier.issn0006-2960
dc.identifier.urihttp://hdl.handle.net/1885/63791
dc.description.abstractMany drug molecules inhibit the conduction of several families of cation channels by binding to a small cavity just below the selectivity filter of the channel protein. The exact mechanisms governing drug-channel binding and the subsequent inhibition of conduction are not well understood. Here the inhibition of two K+channel isoforms, Kv1.2 and KCa3.1, by two drug molecules, lidocaine and TRAM-34, is examined in atomic detail using molecular dynamics simulations. A conserved valine-alanine-valine motif in the inner cavity is found to be crucial for drug binding in both channels, consistent with previous studies of similar systems. Potential of mean force calculations show that lidocaine in its charged form creates an energy barrier of 6 kT for a permeating K+ion when the ion is crossing over the drug, while the neutral form of lidocaine has no significant effect on the energetics of ion permeation. On the other hand, TRAM-34 in the neutral form is able to create a large energy barrier of 10 kT by causing the permeating ion to dehydrate. Our results suggest that TRAM-34 analogues that remain neutral and permeable to membranes under acidic conditions common to inflammation may act as possible drug scaffolds for combating local anesthetic failure in inflammation.
dc.publisherAmerican Chemical Society
dc.sourceBiochemistry
dc.titleMechanisms and energetics of potassium channel block by local anesthetics and antifungal agents
dc.typeJournal article
local.description.notesImported from ARIES
local.identifier.citationvolume53
dc.date.issued2014
local.identifier.absfor030402 - Biomolecular Modelling and Design
local.identifier.absfor030799 - Theoretical and Computational Chemistry not elsewhere classified
local.identifier.ariespublicationu4005981xPUB848
local.type.statusPublished Version
local.contributor.affiliationChen, Rong, College of Medicine, Biology and Environment, ANU
local.contributor.affiliationGryn'ova, Ganna, College of Physical and Mathematical Sciences, ANU
local.contributor.affiliationWu, Yingliang, Wuhan University
local.contributor.affiliationCoote, Michelle, College of Physical and Mathematical Sciences, ANU
local.contributor.affiliationChung, Shin-Ho, College of Medicine, Biology and Environment, ANU
local.description.embargo2037-12-31
local.bibliographicCitation.issue43
local.bibliographicCitation.startpage6786
local.bibliographicCitation.lastpage6792
local.identifier.doi10.1021/bi5009408
local.identifier.absseo970103 - Expanding Knowledge in the Chemical Sciences
local.identifier.absseo970106 - Expanding Knowledge in the Biological Sciences
dc.date.updated2015-12-10T09:21:59Z
local.identifier.scopusID2-s2.0-84908542591
local.identifier.thomsonID000344510300008
CollectionsANU Research Publications

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