A novel hypothesis for the binding mode of HERG channel blockers
Section snippets
Materials and methods
Homology modeling. A homology model of the HERG potassium channel was built on the basis of the 1.7 Å crystal structure (PDB ID code: 1R3J) of the KvAP channel [18], using the homology modeling program, MODELLER v8.0 [19]. A long stretch of amino acids (M579–G603), located at the third extracellular loop of the HERG channel, was not included for the modeling because this region was not present in the template structure and does not appear to be involved in the drug-induced inhibition of the HERG
Results and discussion
To gain new insights into the mechanism(s) by which small molecule inhibitors block HERG channels, we performed a molecular docking simulation. We first built a homology model of the HERG channel based on the KvAP channel structure. We then performed virtual docking of clozapine in the putative binding pocket of the model channel, using the GOLD v2.2 docking program. Our best docking result is shown in Fig. 1. In this prediction, the clozapine made contacts with the S6 transmembrane domain and
Acknowledgment
This work was supported by grants (2003-307 and 2004-307) from the Asan Institute for Life Sciences, Seoul, Korea.
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