Pharmacophore modeling for hERG channel facilitation.
Pharmacophore modeling for hERG channel facilitation.
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DOI：
10.1016/j.bbrc.2011.12.153
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发表时间：
2012-02
影响因子：
3.1
通讯作者：
Yuko Yamakawa;Kazuharu Furutani;A. Inanobe;Y. Ohno;Y. Kurachi
中科院分区：
文献类型：
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作者：
Yuko Yamakawa;Kazuharu Furutani;A. Inanobe;Y. Ohno;Y. Kurachi
人类以太-a-go-go相关基因（hERG）通道在心脏动作电位复极中起关键作用。化合物对hERG通道的非有意阻断可延长心脏动作电位持续时间，诱发心律失常。几种化合物不仅阻断hERG通道，而且在施加去极化电压阶跃后增强通道激活。这被称为促进。在这项研究中，我们试图提取诱导hERG通道促进的化合物的性质。我们首先研究了结构多样的hERG通道阻滞剂对非洲爪蟾卵母细胞的促进作用。13种测定的化合物中有10种允许促进，这表明这是大多数hERG通道阻滞剂的共同作用。我们构建了hERG通道促进的药效团模型。该模型由一个正电离特征和三个疏水特征组成。验证实验表明，该模型较好地描述了促进的构效关系。疏通药效团与hERG通道阻滞药效团的空间分布特征明显不同。因此可以想象，一种化合物与hERG通道的两种不同的相互作用产生两种药理作用，阻断和促进。
Human ether-a-go-go-related gene (hERG) channels play a critical role in cardiac action potential repolarization. The unintended block of hERG channels by compounds can prolong the cardiac action potential duration and induce arrhythmia. Several compounds not only block hERG channels but also enhance channel activation after the application of a depolarizing voltage step. This is referred to as facilitation. In this study, we tried to extract the property of compounds that induce hERG channel facilitation. We first examined the facilitation effects of structurally diverse hERG channel blockers in Xenopus oocytes. Ten of 13 assayed compounds allowed facilitation, suggesting that it is an effect common to most hERG channel blockers. We constructed a pharmacophore model for hERG channel facilitation. The model consisted of one positively ionizable feature and three hydrophobic features. Verification experiments suggest that the model well describes the structure–activity relationship for facilitation. Comparison of the pharmacophore for facilitation with that for hERG channel block showed that the spatial arrangement of features is clearly different. It is therefore conceivable that two different interactions of a compound with hERG channels exert two pharmacological effects, block and facilitation.