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Literature summary for 3.4.24.69 extracted from

  • Pang, Y.P.; Davis, J.; Wang, S.; Park, J.G.; Nambiar, M.P.; Schmidt, J.J.; Millard, C.B.
    Small molecules showing significant protection of mice against botulinum neurotoxin serotype A (2010), PLoS ONE, 5, e10129.
    View publication on PubMedView publication on EuropePMC
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Application

Application Comment Organism
additional information botulinum neurotoxin serotype A causes a life-threatening neuroparalytic disease known as botulism that can afflict large, unprotected populations if the toxin is employed in an act of bioterrorism Clostridium botulinum

Inhibitors

Inhibitors Comment Organism Structure
2-(5-{[1-(4-aminobutyl)-2-phenyl-1H-indol-6-yl]carbonyl}-2-phenylthiophen-3-yl)-N-hydroxyacetamide i.e. 2-(5-[[1-(4-aminobutyl)-2-phenyl-1H-indol-6-yl]carbonyl]-2-phenylthiophen-3-yl)-N-hydroxyacetamide Clostridium botulinum
2-[5-{[1-(4-aminobutyl)-2-phenyl-1H-indol-6-yl]carbonyl}-2-(3-hydroxyphenyl)thiophen-3-yl]-N-hydroxyacetamide i.e. 2-[5-[[1-(4-aminobutyl)-2-phenyl-1H-indol-6-yl]carbonyl]-2-(3-hydroxyphenyl)thiophen-3-yl]-N-hydroxyacetamide, 79% inhibition of BoNTA at 0.02 mM Clostridium botulinum
2-[5-{[1-(4-aminobutyl)-3-fluoro-2-phenyl-1H-indol-6-yl]carbonyl}-2-(3-aminophenyl)thiophen-3-yl]-N-hydroxyacetamide i.e. 2-(5-(1-(4-aminobutyl)-3-fluoro-2-phenyl-1H-indole-6-carbonyl)-2-(3-aminophenyl)thiophen-3-yl)-N-hydroxyacetamide, 47% inhibition of BoNTA at 0.02 mM. The hydroxamate coordinates the zinc ion embedded in the active site and forms a hydrogen bond to Glu224. The cation shows pi-interaction of the thiophene-substituted phenyl group with Arg363. Occurence of pi-pi interactions of the thiophene-substituted phenyl group with Phe194 and Tyr366, of interaction of the ketone oxygen atom with Asp370 that is bridged by at least one water molecule, and of cation-pi and pi-pi interactions of the indole-substituted phenyl group with Lys66 and Gln162, respectively Clostridium botulinum
2-[5-{[1-(4-aminobutyl)-3-fluoro-2-phenyl-1H-indol-6-yl]carbonyl}-2-(4-hydroxyphenyl)thiophen-3-yl]-N-hydroxyacetamide i.e. 2-(5-(1-(4-aminobutyl)-3-fluoro-2-phenyl-1H-indole-6-carbonyl)-2-(4-hydroxyphenyl)thiophen-3-yl)-N-hydroxyacetamide, 82% inhibition of BoNTA at 0.02 mM. The hydroxamate coordinates the zinc ion embedded in the active site and forms a hydrogen bond to Glu224. The cation shows pi-interaction of the thiophene-substituted phenyl group with Arg363. Occurence of pi-pi interactions of the thiophene-substituted phenyl group with Phe194 and Tyr366, of interaction of the ketone oxygen atom with Asp370 that is bridged by at least one water molecule, and of cation-pi and pi-pi interactions of the indole-substituted phenyl group with Lys66 and Gln162, respectively Clostridium botulinum
CpA i.e. [5-(4-chlorobenzoyl)-2-phenylthiophen-3-yl]acetic acid, 15% inhibition of BoNTA at 0.1 mM Clostridium botulinum
additional information development and synthesis of small molecule inhibitors of BoNTA endopeptidase, that antagonize the extracellular or intracellular toxin, in vivo pharmacokinetics in mice, overview. Extended multiple molecular dynamics simulations of inhibitor-enzyme complex formations, overview Clostridium botulinum

Metals/Ions

Metals/Ions Comment Organism Structure
Zn2+ required Clostridium botulinum

Organism

Organism UniProt Comment Textmining
Clostridium botulinum
-
-
-

Synonyms

Synonyms Comment Organism
BoNTA
-
 Clostridium botulinum
botulinum neurotoxin serotype A
-
 Clostridium botulinum

Ki Value [mM]

Ki Value [mM] Ki Value maximum [mM] Inhibitor Comment Organism Structure
0.004
-
 2-[5-{[1-(4-aminobutyl)-2-phenyl-1H-indol-6-yl]carbonyl}-2-(3-hydroxyphenyl)thiophen-3-yl]-N-hydroxyacetamide pH not specified in the publication, temperature not specified in the publication Clostridium botulinum
0.007
-
 2-(5-{[1-(4-aminobutyl)-2-phenyl-1H-indol-6-yl]carbonyl}-2-phenylthiophen-3-yl)-N-hydroxyacetamide pH not specified in the publication, temperature not specified in the publication Clostridium botulinum

General Information

General Information Comment Organism
additional information botulinum neurotoxin serotype A causes a life-threatening neuroparalytic disease known as botulism that can afflict large, unprotected populations if the toxin is employed in an act of bioterrorism Clostridium botulinum