Discovering potassium channel blockers from synthetic compound database by using structure-based virtual screening in conjunction with electrophysiological assay

doi:10.1021/jm060414o

CORC > 上海药物研究所 > 中国科学院上海药物研究所 > 药理学第二研究室

	Discovering potassium channel blockers from synthetic compound database by using structure-based virtual screening in conjunction with electrophysiological assay
	Liu, Hong; Gao, Zhao-Bing; Yao, Zhiyi; Zheng, Suxin; Li, Yang; Zhu, Weiliang; Tan, Xiaojian; Luo, Xiaomin; Shen, Jianhua; Chen, Kaixian
刊名	JOURNAL OF MEDICINAL CHEMISTRY
	2007-01-11
卷号	50 期号:1 页码:83-93
ISSN号	0022-2623
DOI	10.1021/jm060414o
文献子类	Article
英文摘要	Potassium ion (K+) channels are attractive targets for drug discovery because of the essential roles played in biological systems. However, high-throughput screening (HTS) cannot be used to screen K+ channel blockers. To overcome this disadvantage of HTS, we have developed a virtual screening approach for discovering novel blockers of K+ channels. On the basis of a three-dimensional model of the eukaryotic K+ channels, molecular docking-based virtual screening was employed to search the chemical database MDL Available Chemicals Directory (ACD). Compounds were ranked according to their relative binding energy, favorable shape complementarity, and potential to form hydrogen bonds with the outer mouth of the K+ channel model. Twenty candidate compounds selected from the virtual screening were examined using the whole-cell voltage-clamp recording in rat dissociated hippocampal neurons. Among them, six compounds (5, 6, 8, 18-20) potently blocked both the delayed rectifier (I-K) and fast transient K+ currents (I-A). When applied externally, these six compounds preferentially blocked I-K with potencies 2- to 500-fold higher than that of tetraethylammonium chloride. Intracellular application of the six compounds had no effect on both K+ currents. In addition, the interaction models and binding free energy calculations demonstrated that hydrophobic interaction and solvent effects play important roles in the inhibitory activities of these compounds. The results demonstrated that structure-based computer screening strategy could be used to identify novel, structurally diverse compounds targeting the pore binding pocket of the outer mouth of voltage-gated K+ channels. This study provides an alternative way of finding new blockers of voltage-gated K+ channels, while the techniques for high-throughput screening of K+ channel drugs remain in development.
WOS关键词	K+ CHANNEL ; MOLECULAR DOCKING ; CRYSTAL-STRUCTURE ; FORCE-FIELD ; PROTEIN ; PORE ; LIGAND ; PHARMACOLOGY ; SOLUBILITY ; CONDUCTION
WOS研究方向	Pharmacology & Pharmacy
语种	英语
出版者	AMER CHEMICAL SOC
WOS记录号	WOS:000243229500009
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/273357]
专题	药理学第二研究室中科院受体结构与功能重点实验室新药研究国家重点实验室药物发现与设计中心药物化学研究室
通讯作者	Hu, Guo-Yuan
作者单位	Chinese Acad Sci, Shanghai Inst Biol Sci, Shanghai Inst Mat Med, State Key Lab Drug Res,Ctr Drug Discovery & Desig, Shanghai 201203, Peoples R China
推荐引用方式 GB/T 7714	Liu, Hong,Gao, Zhao-Bing,Yao, Zhiyi,et al. Discovering potassium channel blockers from synthetic compound database by using structure-based virtual screening in conjunction with electrophysiological assay[J]. JOURNAL OF MEDICINAL CHEMISTRY,2007,50(1):83-93.
APA	Liu, Hong.,Gao, Zhao-Bing.,Yao, Zhiyi.,Zheng, Suxin.,Li, Yang.,...&Jiang, Hualiang.(2007).Discovering potassium channel blockers from synthetic compound database by using structure-based virtual screening in conjunction with electrophysiological assay.JOURNAL OF MEDICINAL CHEMISTRY,50(1),83-93.
MLA	Liu, Hong,et al."Discovering potassium channel blockers from synthetic compound database by using structure-based virtual screening in conjunction with electrophysiological assay".JOURNAL OF MEDICINAL CHEMISTRY 50.1(2007):83-93.