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

Burnett, JC and Wang, C and Nuss, JE and Nguyen, TL and Hermone, AR and Schmidt, JJ and Gussio, R and Wipf, P and Bavari, S (2009) Pharmacophore-guided lead optimization: The rational design of a non-zinc coordinating, sub-micromolar inhibitor of the botulinum neurotoxin serotype a metalloprotease. Bioorganic and Medicinal Chemistry Letters, 19 (19). 5811 - 5813. ISSN 0960-894X

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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). © 2009.

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Details

Item Type: Article
Status: Published
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Burnett, JC
Wang, C
Nuss, JE
Nguyen, TL
Hermone, AR
Schmidt, JJ
Gussio, R
Wipf, Ppwipf@pitt.eduPWIPF
Bavari, S
Date: 1 October 2009
Date Type: Publication
Journal or Publication Title: Bioorganic and Medicinal Chemistry Letters
Volume: 19
Number: 19
Page Range: 5811 - 5813
DOI or Unique Handle: 10.1016/j.bmcl.2009.01.111
Schools and Programs: Dietrich School of Arts and Sciences > Chemistry
Refereed: Yes
ISSN: 0960-894X
MeSH Headings: 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
PubMed ID: 19703771
Date Deposited: 18 Jun 2013 19:54
Last Modified: 22 Jun 2021 16:55
URI: http://d-scholarship.pitt.edu/id/eprint/18957

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