Ligand- and Structure-Based Virtual Screening for Clathrodin-Derived Human Voltage-Gated Sodium Channel Modulators

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• 作者：Tihomir Toma?i? ; Basil Hartzoulakis ; Nace Zidar ; Fiona Chan ; Robert W. Kirby ; David J. Madge ; Steve Peigneur ; Jan Tytgat ; Danijel Kikelj
• 刊名：Journal of Chemical Information and Modeling
• 出版年：2013
• 出版时间：December 23, 2013
• 年：2013
• 卷：53
• 期：12
• 页码：3223-3232
• 全文大小：475K
• ISSN：1549-960X

文摘

Voltage-gated sodium channels (VGSC) are attractive targets for drug discovery because of the broad therapeutic potential of their modulators. On the basis of the structure of marine alkaloid clathrodin, we have recently discovered novel subtype-selective VGSC modulators I and II that were used as starting points for two different ligand-based virtual screening approaches for discovery of novel VGSC modulators. Similarity searching in the ZINC database of drug-like compounds based on compound I resulted in five state-dependent Na_v1.3 and Na_v1.7 modulators with improved activity compared to I (IC₅₀ < 20 渭M). Compounds 2 and 16 that blocked sodium permeation in Na_v1.7 with IC₅₀ values of 7 and 9 渭M, respectively, are among the most potent clathrodin analogs discovered so far. In the case of compound II, 3D similarity searching in the same database was followed by docking of an enriched compound library into our human Na_v1.4 open-pore homology model. Although some of the selected compounds, e.g., 31 and 32 displayed 21% and 22% inactivated state I_peak block of Na_v1.4 at 10 渭M, respectively, none showed better Na_v1.4 modulatory activity than compound II. Taken together, virtual screening yielded compounds 2 and 16, which represent novel scaffolds for the discovery of human Na_v1.7 modulators.