Side chain flexibilities in the human ether-a-go-go related gene potassium channel (hERG) together with matched-pair binding studies suggest a new binding mode for channel blockers.
Article Details
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Zachariae U, Giordanetto F, Leach AG
Side chain flexibilities in the human ether-a-go-go related gene potassium channel (hERG) together with matched-pair binding studies suggest a new binding mode for channel blockers.
J Med Chem. 2009 Jul 23;52(14):4266-76. doi: 10.1021/jm900002x.
- PubMed ID
- 19534531 [ View in PubMed]
- Abstract
The cardiac hERG K(+) channel constitutes a long-standing and expensive antitarget for the drug industry. From a study of the flexibility of hERG around its internal binding cavity, we have developed a new structural model of drug binding to hERG, which involves binding orthogonal to the pore channel and therefore can exploit the up to 4-fold symmetry of the tetrameric channel. This binding site has a base formed by four tyrosine side chains that complement reported ligand-based pharmacophores. The model is able to rationalize reduced hERG potency in matched molecular pair studies and suggests design guidelines to optimize against hERG not relying simply on lipophilicity reduction. The binding model also suggests a molecular mechanism for the link between high-affinity hERG binding and C-type inactivation.
DrugBank Data that Cites this Article
- Binding Properties
Drug Target Property Measurement pH Temperature (°C) Cisapride Potassium voltage-gated channel subfamily H member 2 IC 50 (nM) 6.7 N/A N/A Details Pimozide Potassium voltage-gated channel subfamily H member 2 IC 50 (nM) 54.6 N/A N/A Details Sertindole Potassium voltage-gated channel subfamily H member 2 IC 50 (nM) 14.7 N/A N/A Details Terfenadine Potassium voltage-gated channel subfamily H member 2 IC 50 (nM) 213 N/A N/A Details Thioridazine Potassium voltage-gated channel subfamily H member 2 IC 50 (nM) 33.2 N/A N/A Details