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. 2012 Apr 2;3(5):387-91.
doi: 10.1021/ml200312s. eCollection 2012 May 10.

Fungal bis-Naphthopyrones as Inhibitors of Botulinum Neurotoxin Serotype A

John H Cardellina 2nd  1 , Virginia I Roxas-Duncan  1 , Vicki Montgomery  1 , Vanessa Eccard  1 , Yvette Campbell  1 , Xin Hu  2 , Ilja Khavrutskii  2 , Gregory J Tawa  2 , Anders Wallqvist  2 , James B Gloer  3 , Nisarga L Phatak  3 , Ulrich Höller  3 , Ashish G Soman  3 , Biren K Joshi  3 , Sara M Hein  3 , Donald T Wicklow  4 , Leonard A Smith  5
Affiliations

Fungal bis-Naphthopyrones as Inhibitors of Botulinum Neurotoxin Serotype A

John H Cardellina 2nd et al. ACS Med Chem Lett. .

Abstract

An in silico screen of the NIH Molecular Library Small Molecule Repository (MLSMR) of ∼350000 compounds and confirmatory bioassays led to identification of chaetochromin A (1) as an inhibitor of botulinum neurotoxin serotype A (BoNT A). Subsequent acquisition and testing of analogues of 1 uncovered two compounds, talaroderxines A (2) and B (3), with improved activity. These are the first fungal metabolites reported to exhibit BoNT/A inhibitory activity.

Keywords: binding free energy; botulinum neurotoxin serotype A; chaetochromin; in silico screen; natural products; talaroderxine; thermodynamic integration.

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Figures

Chart 1
Chart 1
Figure 1
Figure 1
Proposed binding mode of (A) chaetochromin A (1), (B) talaroderxine A (2), and (C) talaroderxine B (3) in the active site of BoNT/A. The Zn2+ ion is shown as a magenta sphere, carbon atoms of the ligands are depicted in yellow, and those of the active site residues are in cyan. The molecular surface of the pocket is shown in a transparent light gray color. For clarity, only polar hydrogens are shown. Panels A and B depict the most populated cluster centers from SRTI-HREX simulations, whereas panel C is the result of docking.
See this image and copyright information in PMC

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