Drug block of the hERG potassium channel: Insight from modeling

• DOI: 10.1002/prot.21400
• Publication Date: 2007-04-19T20:18:31Z
• Authors: Phillip J. Stansfeld; Peter Gedeck; Martin Gosling; Brian Cox; John S. Mitcheson; Michael J. Sutcliffe
• Keywords: hERG; KcsA potassium channel

Abstract Many commonly used, structurally diverse, drugs block the human ether‐a‐go‐go‐related gene (hERG) K + channel to cause acquired long QT syndrome, which can lead sudden death via lethal cardiac arrhythmias. This undesirable side effect is a major hurdle in development of safe drugs. To gain insight about structure hERG and nature drug we have produced structural models pore domain, into each docked set 20 blockers. In absence an experimentally determined three‐dimensional hERG, was validated against site‐directed mutagenesis data. First, were open closed states, based on homology with prokaryotic crystal structures. The modeled complexes partial agreement improve data, KcsA‐based model refined by rotating four copies S6 transmembrane helix half residue position toward C‐terminus, so as place all residues known be involved binding positions lining central cavity. produces that are consistent data for smaller, but not larger, ligands. Larger ligands could accommodated following refinement this enlarging cavity using inherent flexibility glycine hinge (Gly648) S6, produce results experimental majority tested. Proteins 2007. © 2007 Wiley‐Liss, Inc.