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Exploring blocker binding to a homology model of the open hERG K + channel using docking and molecular dynamics methods
Author(s) -
Österberg Fredrik,
Åqvist Johan
Publication year - 2005
Publication title -
febs letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.593
H-Index - 257
eISSN - 1873-3468
pISSN - 0014-5793
DOI - 10.1016/j.febslet.2005.04.039
Subject(s) - herg , docking (animal) , homology modeling , chemistry , molecular dynamics , alanine scanning , affinities , stereochemistry , potassium channel , binding site , molecular model , biophysics , computational chemistry , biochemistry , biology , mutation , mutagenesis , enzyme , medicine , nursing , gene
Binding of blockers to the human voltage‐gated hERG potassium channel is studied using a combination of homology modelling, automated docking calculations and molecular dynamics simulations, where binding affinities are evaluated using the linear interaction energy method. A homology model was constructed based on the available crystal structure of the bacterial KvAP channel and the affinities of a series of sertindole analogues predicted using this model. The calculations reproduce the relative binding affinities of these compounds very well and indicate that both polar interactions near the intracellular opening of the selectivity filter as well as hydrophobic complementarity in the region around F656 are important for blocker binding. These results are consistent with recent alanine scanning mutation experiments on the blocking of the hERG channel by other compounds.