Fungal bis-Naphthopyrones as Inhibitors of Botulinum Neurotoxin Serotype A

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 t...

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Main Authors: Cardellina II, John H, Roxas-Duncan, Virginia I, Montgomery, Vicki, Eccard, Vanessa, Campbell, Yvette, Hu, Xin, Khavrutskii, Ilja, Tawa, Gregory J, Wallqvist, Anders, Gloer, James B, Phatak, Nisarga L, Hoeller, Ulrich, Soman, Ashish G, Joshi, Biren K, Hein, Sara M, Wicklow, Donald T, Smith, Leonard A
Format: Report
Language:English
Subjects:
BINDING FREE ENERGY
BIOASSAY
Biochemistry
BONTS(BOTULINUM NEUROTOXINS)
BOTULINUM NEUROTOXIN SEROTYPE A
CHAETOCHROMIN
CLOSTRIDIUM BOTULINUM
COMPARATIVE TESTING
FREE ENERGY
FUNGAL METABOLITES
FUNGI
IN SILICO SCREENS
INHIBITORS
LIGANDS
METABOLITES
Microbiology
MLSMR(MOLECULAR LIBRARY SMALL MOLECULE REPOSITORY)
NATURAL PRODUCTS
NEUROTOXINS
Pharmacology
TALARODERXINE
THERMODYNAMIC INTEGRATION
THERMODYNAMIC PROPERTIES
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Summary: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. Published in ACS Medicinal Chemistry Letters, v3 p387-391, 2 Apr 2012.