1. Target-induced formation of neuraminidase inhibitors from in vitro virtual combinatorial libraries.
- Author
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Hochgürtel M, Kroth H, Piecha D, Hofmann MW, Nicolau C, Krause S, Schaaf O, Sonnenmoser G, and Eliseev AV
- Subjects
- Aldehydes chemistry, Aldehydes metabolism, Amines chemistry, Amines metabolism, Binding Sites, Influenza A virus classification, Molecular Structure, Neuraminidase chemistry, Neuraminidase metabolism, Thermodynamics, Combinatorial Chemistry Techniques methods, Drug Design, Enzyme Inhibitors chemistry, Enzyme Inhibitors metabolism, Influenza A virus enzymology, Neuraminidase antagonists & inhibitors
- 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.
- Published
- 2002
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