A two-state homology model of the hERG K+ channel: application to ligand binding.
A two-state homology model of the hERG K+ channel: application to ligand binding.
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DOI：
10.1016/j.bmcl.2005.01.008
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发表时间：
2005-03
影响因子：
2.7
通讯作者：
R. Rajamani;B. Tounge;J. Li;C. Reynolds
中科院分区：
文献类型：
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作者：
R. Rajamani;B. Tounge;J. Li;C. Reynolds
基于可用K+通道结构的同源模型已用于构建hERG心脏K+通道的多状态表示。这些状态用于捕获通道的灵活性。我们表明，这种灵活性是必不可少的，以正确地模拟一组不同的配体的结合亲和力。使用这种多状态方法，为一组已知的hERG通道结合剂构建结合亲和力模型。预测的pIC_（50）值与实验值吻合较好（RMSD：0.56kcal/mol）。此外，这些计算提供了与已发表的突变研究一致的结合配体的结构。这些计算的配体结合的复合物结构可用于指导具有降低的hERG倾向的类似物的合成。
Homology models based on available K+channel structures have been used to construct a multiple state representation of the hERG cardiac K+channel. These states are used to capture the flexibility of the channel. We show that this flexibility is essential in order to correctly model the binding affinity of a set of diverse ligands. Using this multiple state approach, a binding affinity model was constructed for set of known hERG channel binders. The predicted pIC50s are in good agreement with experiment (RMSD: 0.56kcal/mol). In addition, these calculations provide structures for the bound ligands that are consistent with published mutation studies. These computed ligand bound complex structures can be used to guide synthesis of analogs with reduced hERG liability.