The hERG potassium channel and drug trapping: insight from docking studies with propafenone derivatives.
The inner cavity of the hERG potassium ion channel can accommodate large, structurally diverse compounds that can be trapped in the channel by closure of the activation gate. A small set of propafenone derivatives was synthesized, and both use-dependency and recovery from block were tested in order to gain insight into the behavior of these compounds with respect to trapping and non-trapping. Ligand-protein docking into homology models of the closed and open state of the hERG channel provides the first evidence for the molecular basis of drug trapping.
Thai
Khac-Minh
KM
Department of Medicinal Chemistry, Emerging Field Pharmacoinformatics, University of Vienna, Althanstrasse 14, 1090 Wien, Austria.
Windisch
Andreas
A
Stork
Daniela
D
Weinzinger
Anna
A
Schiesaro
Andrea
A
Guy
Robert H
RH
Timin
Eugen N
EN
Hering
Steffen
S
Ecker
Gerhard F
GF
D000889:Anti-Arrhythmia Agents / Q000737:chemistry* / Q000494:pharmacology*; D051638:Ether-A-Go-Go Potassium Channels / Q000737:chemistry* / Q000378:metabolism*; D006801:Humans; D008958:Models, Molecular; D011405:Propafenone / Q000737:chemistry* / Q000494:pharmacology*; D011485:Protein Binding; D011487:Protein Conformation
D000889:Anti-Arrhythmia Agents; D051638:Ether-A-Go-Go Potassium Channels; D011405:Propafenone