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Ligand- and structure-based virtual screening for clathrodin-derived human voltage-gated sodium channel modulators
Tomašic, T.; Hartzoulakis, B.; Zidar, N.; Chan, F.; Kirby, R.W.; Madge, D.J.; Peigneur, S.; Tytgat, J.; Kikelj, D. (2013). Ligand- and structure-based virtual screening for clathrodin-derived human voltage-gated sodium channel modulators. Journal of Chemical Information and Modeling 53(12): 3223-3232. https://hdl.handle.net/10.1021/ci400505e
In: Journal of Chemical Information and Modeling. AMER CHEMICAL SOC: Washington. ISSN 1549-9596; e-ISSN 1549-960X
Peer reviewed article  

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  • Tomašic, T.
  • Hartzoulakis, B.
  • Zidar, N.
  • Chan, F.
  • Kirby, R.W.
  • Madge, D.J.
  • Peigneur, S.
  • Tytgat, J.
  • Kikelj, D.

Abstract
    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 Nav1.3 and Nav1.7 modulators with improved activity compared to I (IC50 < 20 μM). Compounds 2 and 16 that blocked sodium permeation in Nav1.7 with IC50 values of 7 and 9 μM, 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 Nav1.4 open-pore homology model. Although some of the selected compounds, e.g., 31 and 32 displayed 21% and 22% inactivated state Ipeak block of Nav1.4 at 10 μM, respectively, none showed better Nav1.4 modulatory activity than compound II. Taken together, virtual screening yielded compounds 2 and 16, which represent novel scaffolds for the discovery of human Nav1.7 modulators.

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