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

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Burnett JC, Wang C, Nuss JE, Nguyen TL, Hermone AR, Schmidt JJ, Gussio R, Wipf P, Bavari S

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.

PubMed ID
19703771 [ View in PubMed
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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).

DrugBank Data that Cites this Article

Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
(2E)-3-(2,4-DICHLOROPHENYL)-N-HYDROXYACRYLAMIDEBotulinum neurotoxin type AIC 50 (nM)>29000N/AN/ADetails