期刊
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
卷 55, 期 32, 页码 9422-9426出版社
WILEY-V C H VERLAG GMBH
DOI: 10.1002/anie.201603074
关键词
dynamic combinatorial chemistry; fragment-based drug design; inhibitors; proteases; X-ray diffraction
资金
- Netherlands Organisation for Scientific Research (NWO-CW, VIDI)
- Dutch Ministry of Education, Culture, Science [024.001.035]
Fragment-based drug design (FBDD) affords active compounds for biological targets. While there are numerous reports on FBDD by fragment growing/optimization, fragment linking has rarely been reported. Dynamic combinatorial chemistry (DCC) has become a powerful hit-identification strategy for biological targets. We report the synergistic combination of fragment linking and DCC to identify inhibitors of the aspartic protease endothiapepsin. Based on X-ray crystal structures of endothiapepsin in complex with fragments, we designed a library of bis-acylhydrazones and used DCC to identify potent inhibitors. The most potent inhibitor exhibits an IC50 value of 54 nM, which represents a 240-fold improvement in potency compared to the parent hits. Subsequent X-ray crystallography validated the predicted binding mode, thus demonstrating the efficiency of the combination of fragment linking and DCC as a hit-identification strategy. This approach could be applied to a range of biological targets, and holds the potential to facilitate hit-to-lead optimization.
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