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ACS Med Chem Lett. 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.

Author information

1
Division of Integrated Toxicology, U.S. Army Medical Research Institute of Infectious Diseases , Frederick, Maryland 21702-5011.
2
Biotechnology High Performance Computer Software Applications Institute, Telemedicine and Advanced Technology Research Center, U.S. Army Medical Research and Materiel Command , Frederick, Maryland 21702.
3
Department of Chemistry, University of Iowa , Iowa City, Iowa 52242-1294.
4
Bacterial Foodborne Pathogens and Mycology Research Unit, Agricultural Research Service, U.S. Department of Agriculture , Peoria, Illinois 61604.
5
Senior Research Scientist for Medical Countermeasures Technology, U.S. Army Medical Research Institute of Infectious Diseases , Frederick, Maryland 21702-5011.

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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