Evaluation of adamantane hydroxamates as botulinum neurotoxin inhibitors: synthesis, crystallography, modeling, kinetic and cellular based studies.

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Silhar P, Silvaggi NR, Pellett S, Capkova K, Johnson EA, Allen KN, Janda KD

Evaluation of adamantane hydroxamates as botulinum neurotoxin inhibitors: synthesis, crystallography, modeling, kinetic and cellular based studies.

Bioorg Med Chem. 2013 Mar 1;21(5):1344-8. doi: 10.1016/j.bmc.2012.12.001. Epub 2012 Dec 20.

PubMed ID

23340139 [ View in PubMed

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Abstract

Botulinum neurotoxins (BoNTs) are the most lethal biotoxins known to mankind and are responsible for the neuroparalytic disease botulism. Current treatments for botulinum poisoning are all protein based and thus have a limited window of treatment opportunity. Inhibition of the BoNT light chain protease (LC) has emerged as a therapeutic strategy for the treatment of botulism as it may provide an effective post exposure remedy. Using a combination of crystallographic and modeling studies a series of hydroxamates derived from 1-adamantylacetohydroxamic acid (3a) were prepared. From this group of compounds, an improved potency of about 17-fold was observed for two derivatives. Detailed mechanistic studies on these structures revealed a competitive inhibition model, with a K(i)=27 nM, which makes these compounds some of the most potent small molecule, non-peptidic BoNT/A LC inhibitors reported to date.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
(2E)-3-(2,4-DICHLOROPHENYL)-N-HYDROXYACRYLAMIDE	Botulinum neurotoxin type A	Ki (nM)	300	N/A	N/A	Details