Exploring blocker binding to a homology model of the open hERG K+ channel using docking and molecular dynamics methods
Exploring blocker binding to a homology model of the open hERG K+ channel using docking and molecular dynamics methods
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DOI：
10.1016/j.febslet.2005.04.039
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发表时间：
2005-05
期刊：
影响因子：
3.5
通讯作者：
F. Österberg;J. Åqvist
中科院分区：
文献类型：
--
作者：
F. Österberg;J. Åqvist
采用同源建模、自动对接计算和分子动力学模拟相结合的方式研究阻断剂与人电压门控 hERG 钾通道的结合，其中使用线性相互作用能量方法评估结合亲和力。基于细菌 KvAP 通道的可用晶体结构和使用该模型预测的一系列舍吲哚类似物的亲和力构建了同源模型。计算很好地再现了这些化合物的相对结合亲和力，并表明选择性过滤器细胞内开口附近的极性相互作用以及 F656 周围区域的疏水互补性对于阻断剂结合都很重要。这些结果与最近其他化合物阻断 hERG 通道的丙氨酸扫描突变实验一致。
Binding of blockers to the human voltage-gated hERG potassium channel is studied using a combination of homology modelling, automated docking calculations and molecular dynamics simulations, where binding affinities are evaluated using the linear interaction energy method. A homology model was constructed based on the available crystal structure of the bacterial KvAP channel and the affinities of a series of sertindole analogues predicted using this model. The calculations reproduce the relative binding affinities of these compounds very well and indicate that both polar interactions near the intracellular opening of the selectivity filter as well as hydrophobic complementarity in the region around F656 are important for blocker binding. These results are consistent with recent alanine scanning mutation experiments on the blocking of the hERG channel by other compounds.