Target-induced formation of neuraminidase inhibitors from in vitro virtual combinatorial libraries.
Neuraminidase, a key enzyme responsible for influenza virus propagation, has been used as a template for selective synthesis of small subsets of its own inhibitors from theoretically highly diverse dynamic combinatorial libraries. We show that the library building blocks, aldehydes and amines, form significant amounts of the library components resulting from their coupling by reductive amination only in the presence of the enzyme. The target amplifies the best hits at least 120-fold. The dynamic libraries synthesized and screened in such an in vitro virtual mode form the components that possess high inhibitory activity, as confirmed by enzyme assays with independently synthesized individual compounds.
Hochgürtel
Matthias
M
Therascope AG, Im Neuenheimer Feld 584, 69120 Heidelberg, Germany.
Kroth
Heiko
H
Piecha
Dorothea
D
Hofmann
Michael W
MW
Nicolau
Claude
C
Krause
Sonja
S
Schaaf
Otmar
O
Sonnenmoser
Gabriele
G
Eliseev
Alexey V
AV
D000447:Aldehydes / Q000737:chemistry / Q000378:metabolism; D000588:Amines / Q000737:chemistry / Q000378:metabolism; D001665:Binding Sites; D020650:Combinatorial Chemistry Techniques / Q000379:methods*; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000378:metabolism*; D009980:Influenza A virus / Q000145:classification / Q000201:enzymology*; D015394:Molecular Structure; D009439:Neuraminidase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D013816:Thermodynamics
D000447:Aldehydes; D000588:Amines; D004791:Enzyme Inhibitors; D009439:Neuraminidase