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A drug pocket at the lipid bilayer-potassium channel interface.

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.

SUBMITTER: Ottosson NE

PROVIDER: S-EPMC5656419 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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A drug pocket at the lipid bilayer-potassium channel interface.

Ottosson Nina E NE Silverå Ejneby Malin M Wu Xiongyu X Yazdi Samira S Konradsson Peter P Lindahl Erik E Elinder Fredrik F

Science advances 20171025 10

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 dehydroabieti ...[more]

PMID: 29075666

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