title: Target-induced formation of neuraminidase inhibitors from in vitro virtual combinatorial libraries.
abstract: 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.
authors.affiliation: Therascope AG, Im Neuenheimer Feld 584, 69120 Heidelberg, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Hochgürtel
authors.forename: Heiko
authors.initials: H
authors.lastname: Kroth
authors.forename: Dorothea
authors.initials: D
authors.lastname: Piecha
authors.forename: Michael W
authors.initials: MW
authors.lastname: Hofmann
authors.forename: Claude
authors.initials: C
authors.lastname: Nicolau
authors.forename: Sonja
authors.initials: S
authors.lastname: Krause
authors.forename: Otmar
authors.initials: O
authors.lastname: Schaaf
authors.forename: Gabriele
authors.initials: G
authors.lastname: Sonnenmoser
authors.forename: Alexey V
authors.initials: AV
authors.lastname: Eliseev
mesh_terms: 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
chemical_list: D000447:Aldehydes; D000588:Amines; D004791:Enzyme Inhibitors; D009439:Neuraminidase