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

J C Burnett; C Wang; J E Nuss; T L Nguyen; A R Hermone; J J Schmidt; R Gussio; P Wipf; S Bavari

doi:10.1016/j.bmcl.2009.01.111

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

Bioorg Med Chem Lett. 2009 Oct 1;19(19):5811-3. doi: 10.1016/j.bmcl.2009.01.111. Epub 2009 Feb 13.

Authors

J C Burnett¹, C Wang, J E Nuss, T L Nguyen, A R Hermone, J J Schmidt, R Gussio, P Wipf, S Bavari

Affiliation

¹ SAIC Frederick, Inc., Target Structure-Based Drug Discovery Group, Frederick, National Cancer Institute at Frederick, P.O. Box B, Frederick, MD 21702, United States. burnett.james@mail.nih.gov

PMID: 19703771
DOI: 10.1016/j.bmcl.2009.01.111

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).

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

Neurotoxins
Protease Inhibitors
Botulinum Toxins, Type A
Zinc

Grants and funding

N01-CO-12400/CO/NCI NIH HHS/United States