Back to Archived Journals » Open Access Bioinformatics » Volume 2

Analysis of botulinum neurotoxin serotype A metalloprotease inhibitors: analogs of a chemotype for therapeutic  development in the context of a three-zone pharmacophore

Authors Burnett JC, Li B, Pai R, Cardinale SC, Butler MM, Peet NP, Moir D, Bavari S, Bowlin T

Published 7 April 2010 Volume 2010:2 Pages 11—18


Review by Single anonymous peer review

Peer reviewer comments 2

Download Article [PDF] 

James C Burnett1, Bing Li2, Ramdas Pai2, Steven C Cardinale2, Michelle M Butler2, Norton P Peet2, Donald Moir2, Sina Bavari3, Terry Bowlin2

1Target, Structure-Based Drug Discovery Group, SAIC-Frederick, Inc., National Cancer Institute at Frederick; Frederick, MD 21702, USA; 2Microbiotix, Inc., Worcester, MA 01605, USA; 3Division of Integrated Toxicology,  United States Army Medical Research Institute of Infectious Diseases, Frederick, MD 21702, USA

Abstract: Botulinum neurotoxins (BoNTs), and in particular serotype A, are the most poisonous of known biological substances, and are responsible for the flaccid paralysis of the disease state botulism. Because of the extreme toxicity of these enzymes, BoNTs are considered highest priority biothreat agents. To counter BoNT serotype A (BoNT/A) poisoning, the discovery and development of small molecule, drug like inhibitors as post intoxication therapeutic agents is being pursued. Specifically, we are focusing on inhibitors of the BoNT/A light chain (LC) (ie, a metalloprotease) subunit, since such compounds can enter neurons and provide post intoxication protection of the enzyme target substrate. To aid/facilitate this drug development effort, a pharmacophore for inhibition of the BoNT/A LC subunit was previously developed, and is continually being refined via the incorporation of novel and diverse inhibitor chemotypes. Here, we describe several analogs of a promising therapeutic chemotype in the context of the pharmacophore for BoNT/A LC inhibition. Specifically, we describe: 1) the pharmacophoric ‘fits’ of the analogs and how these ‘fits’ rationalize the in vitro inhibitory potencies of the analogs, and 2) pharmacophore refinement via the inclusion of new components from the most potent of the presented analogs.

Keywords: botulinum, neurotoxin, inhibitor, pharmacophore, metalloprotease, biothreat

Creative Commons License This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at and incorporate the Creative Commons Attribution - Non Commercial (unported, v3.0) License. By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms.

Download Article [PDF]