The synergic modeling for the binding of fluoroquinolone antibiotics to the hERG potassium channel

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:23

Article

Ryu, Sunghi¹  Imai, Yumi N.²  Oiki, Shigetoshi³ 

[1] Takeda Pharmaceut Co Ltd, CMC Ctr, Osaka 5328686, Japan

[2] Takeda Pharmaceut Co Ltd, Div Pharmaceut Res, Fujisawa, Kanagawa 2518555, Japan

[3] Univ Fukui, Fac Med Sci, Dept Mol Physiol & Biophys, Fukui 9101193, Japan

关键词: hERG liability;    Tandem dimer mutant;    Binding mode prediction;    Electrophysiology;    Carboxyl group;   

DOI  :  10.1016/j.bmcl.2013.04.074

来源: Elsevier

【 摘 要 】

The fluoroquinolone antibiotic binding site in the hERG potassium channel was examined for the residues involved and their position in the tetrameric channel. The blocking effect of the two fluoroquinolones levofloxacin and sparfloxacin to tandem dimers of the hERG mutants were evaluated electrophysiologically. The results indicated that two Tyr652s in the neighboring subunits and one or two Phe656s in the diagonal subunits contributed to the blockade in the case of both compounds, and Ser624 was also involved. The docking studies suggested that the protonated carboxyl group in the compounds strongly interacts with Phe656 as a pi acceptor. (c) 2013 The Authors. Published by Elsevier Ltd. All rights reserved.

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