A drug pocket at the lipid bilayer-potassium channel interface

Science Advances
Nina E OttossonFredrik Elinder

Abstract

Many pharmaceutical drugs against neurological and cardiovascular disorders exert their therapeutic effects by binding to specific sites on voltage-gated ion channels of neurons or cardiomyocytes. To date, all molecules targeting known ion channel sites bind to protein pockets that are mainly surrounded by water. We describe a lipid-protein drug-binding pocket of a potassium channel. We synthesized and electrophysiologically tested 125 derivatives, analogs, and related compounds to dehydroabietic acid. Functional data in combination with docking and molecular dynamics simulations mapped a binding site for small-molecule compounds at the interface between the lipid bilayer and the transmembrane segments S3 and S4 of the voltage-sensor domain. This fundamentally new binding site for small-molecule compounds paves the way for the design of new types of drugs against diseases caused by altered excitability.

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Citations

Apr 8, 2018·The Journal of General Physiology·Malin Silverå EjnebyFredrik Elinder
Jul 14, 2018·The Journal of General Physiology·Sara I LiinFredrik Elinder
Apr 26, 2020·International Journal of Molecular Sciences·Maria Cristina D'AdamoPaola Imbrici
Sep 5, 2020·Cell Research·Xiaoxiao LiJiangtao Guo
Jun 6, 2020·Frontiers in Pharmacology·Kenny M Van TheemscheAlain J Labro
Mar 9, 2021·The Journal of General Physiology·Malin Silverå EjnebyLucie Delemotte
Jul 16, 2019·Biophysical Journal·Hongbo ChenKatherine A Henzler-Wildman
Oct 15, 2020·Proceedings of the National Academy of Sciences of the United States of America·Malin Silverå EjnebyFredrik Elinder
Jun 10, 2020·The Journal of Physical Chemistry. B·Zhiqiang ShenYing Li

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Software Mentioned

CHARMM
Clampfit
Marvin Suite
CHARMM ( Mechanics MATCH )
pClamp
GROMACS
GraphPad Prism
AMBER
Calculation Plugin
Delphi

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