5 years ago

Target-directed Dynamic Combinatorial Chemistry: A Study on Potentials and Pitfalls as Exemplified on a Bacterial Target

Target-directed Dynamic Combinatorial Chemistry: A Study on Potentials and Pitfalls as Exemplified on a Bacterial Target
Beat Ernst, Marleen Silbermann, Priska Frei, Tobias Mühlethaler, Deniz Eriş, Lijuan Pang, Oliver Schwardt
Target-directed dynamic combinatorial chemistry (DCC) is an emerging technique for the efficient identification of inhibitors of pharmacologically relevant targets. In this contribution, we present an application for a bacterial target, the lectin FimH, a crucial virulence factor of uropathogenic E. coli being the main cause of urinary tract infections. A small dynamic library of acylhydrazones was formed from aldehydes and hydrazides and equilibrated at neutral pH in presence of aniline as nucleophilic catalyst. The major success factors turned out to be an accordingly adjusted ratio of scaffolds and fragments, an adequate sample preparation prior to HPLC analysis, and the data processing. Only then did the ranking of the dynamic library constituents correlate well with affinity data. Furthermore, as a support of DCC applications especially to larger libraries, a new protocol for improved hit identification was established. Right on target: A target-directed dynamic combinatorial chemistry approach based on reversible acylhydrazones allowed the identification of high-affinity ligands for a bacterial adhesin. The ratio of building blocks, sample preparation before HPLC analysis, and data procession has proven to be essential for success. Furthermore, removal of unbound ligands before analysis greatly contributed to the identification of good binders.

Publisher URL: http://onlinelibrary.wiley.com/resolve/doi

DOI: 10.1002/chem.201701601

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