Frei Priska, Pang Lijuan, Silbermann Marleen, Eriş Deniz, Mühlethaler Tobias, Schwardt Oliver, Ernst Beat
Institute of Molecular Pharmacy, Pharmacenter, University of Basel, Klingelbergstrasse 50, 4056, Basel, Switzerland.
Chemistry. 2017 Aug 25;23(48):11570-11577. doi: 10.1002/chem.201701601. Epub 2017 Aug 4.
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.
靶向动态组合化学（DCC）是一种用于高效鉴定药理学相关靶点抑制剂的新兴技术。在本论文中，我们展示了该技术在细菌靶点——凝集素FimH上的应用，FimH是致病性大肠杆菌的关键毒力因子，也是尿路感染的主要病因。由醛和酰肼形成了一个小型动态酰腙文库，并在苯胺作为亲核催化剂存在的中性pH条件下达到平衡。主要的成功因素包括相应调整的支架和片段比例、HPLC分析前充分的样品制备以及数据处理。只有这样，动态文库成分的排序才与亲和力数据良好相关。此外，作为对DCC应用尤其是对更大文库应用的支持，建立了一种改进的命中鉴定新方案。
