Structure‐Based Virtual Screening and Electrophysiological Evaluation of New Chemotypes of Kv1.5 Channel Blockers
Structure‐Based Virtual Screening and Electrophysiological Evaluation of New Chemotypes of Kv1.5 Channel Blockers
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Kv1.5 通道阻断剂新化学型的基于结构的虚拟筛选和电生理学评估
DOI：
10.1002/cmdc.201000162
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发表时间：
2010
期刊：
影响因子：
3.4
通讯作者：
Q. You
中科院分区：
文献类型：
--
作者：
Qian Yang;D. Fedida;Hongjian Xu;B. Wang;Lupei Du;Xiaojian Wang;Minyong Li;Q. You
心房颤动（AF）是最常见的非致命性心律失常，与心力衰竭和卒中风险增加相关。考虑到目前使用的抗心律失常药物引起的心室副作用，Kv1.5通道阻滞剂由于其对心房电生理的选择性作用而引起了大量的讨论。在本文中，我们报告了通过基于结构的虚拟筛选和计算机模拟药物性质预测（包括六个评分函数）以及电生理学评价相结合鉴定的Kv1.5通道阻滞剂的新化学型。 其中，18种化合物中有5种在10 μM下表现出> 50%的阻断率，并且具有不同于传统Kv1.5通道阻滞剂的结构特征。 这些新型支架可以作为进一步优化和SAR研究的目标，以发现治疗AF的选择性药物。
Atrial fibrillation (AF) is the most prevalent nonfatal cardiac rhythm disorder associated with an increased risk of heart failure and stroke. Considering the ventricular side effects induced by anti‐arrhythmic agents in current use, Kv1.5 channel blockers have attracted a great deal of deliberation owing to their selective actions on atrial electrophysiology. Herein we report new chemotypes of Kv1.5 channel blockers that were identified through a combination of structure‐based virtual screening and in silico druglike property prediction including six scoring functions, as well as electrophysiological evaluation. Among them, five of the 18 compounds exhibited >50 % blockade ratio at 10 μM, and have structural features different from conventional Kv1.5 channel blockers. These novel scaffolds could serve as hits for further optimization and SAR studies for the discovery of selective agents to treat AF.