A novel structure-based virtual screening model for the hERG channel blockers
A novel structure-based virtual screening model for the hERG channel blockers
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DOI：
10.1016/j.bbrc.2007.02.068
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发表时间：
2007-04-20
影响因子：
3.1
通讯作者：
Xia, Lin
中科院分区：
文献类型：
--
作者：
Du, Lupei;Li, Minyong;Xia, Lin
hERG 钾通道是心脏复极的关键效应器，阻断该通道可能导致心律失常。因此，hERG 通道阻断对于潜在的促心律失常作用起着重要作用。在本报告中，结合同源建模、分子对接和分子模拟研究了阻断剂与 hERG 钾通道的结合，其中使用 GoldScore 适应性的线性回归模型评估阻断活性。这种基于结构的虚拟筛选模型能够估计 hERG 钾通道的多种配体的 pIC(50) 值。配体的对接姿势也与已发表的突变一致。因此，这种预测 hERG 通道阻断的模型有可能为评估新化学实体的心脏责任提供具有成本效益的虚拟筛选工具。 (c) 2007 Elsevier Inc. 保留所有权利。
The hERG potassium channel is a key effector of cardiac repolarization and the blockade of this channel could cause arrhythmia. Thus, hERG channel blockade plays an important role for the potential pro-arrhythmic liability. In this report, binding of blockers to the hERG potassium channel is investigated using a combination of homology modeling, molecular docking, and molecular simulations, where blockade activities are evaluated using the linear regression model of GoldScore fitness. This structure-based virtual screening model is able to estimate the pIC(50) value of a wide range of ligands for the hERG potassium channel. The docked poses for ligands are also consistent with published mutation. Therefore, this model for the prediction of hERG channel blockade has the potential to provide cost-effective virtual screening tools for the evaluation of the cardiac liability of new chemical entities. (c) 2007 Elsevier Inc. All rights reserved.