Pharmacophore-guided lead optimization: the rational design of a non-zinc coordinating, sub-micromolar inhibitor of the botulinum neurotoxin serotype a metalloprotease.

Abstract

Botulinum neurotoxins, responsible for the neuroparalytic syndrome botulism, are the deadliest of known biological toxins. The work described in this study was based on a three-zone pharmacophore model for botulinum neurotoxin serotype A light chain inhibition. Specifically, the pharmacophore defined a separation between the overlaps of several different, non-zinc(II)-coordinating small molecule chemotypes, enabling the design and synthesis of a new structural hybrid possessing a Ki=600 nM (+/-100 nM).

• Authors: J C Burnett, C Wang, J E Nuss, T L Nguyen, A R Hermone, J J Schmidt, R Gussio, P Wipf, S Bavari
• Journal: Bioorganic & medicinal chemistry letters (Bioorg Med Chem Lett) Vol. 19 Issue 19 Pg. 5811-3 (Oct 01 2009) ISSN: 1464-3405 [Electronic] England
• PMID: 19703771 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Neurotoxins
• Protease Inhibitors
• Botulinum Toxins, Type A
• Zinc

Topics

• Botulinum Toxins, Type A (antagonists & inhibitors, metabolism)
• Drug Design
• Neurotoxins (antagonists & inhibitors, metabolism)
• Protease Inhibitors (chemical synthesis, chemistry, pharmacology)
• Stereoisomerism
• Structure-Activity Relationship
• Zinc (chemistry)