Fragment Linking and Optimization of Inhibitors of the Aspartic Protease Endothiapepsin: Fragment-Based Drug Design Facilitated by Dynamic Combinatorial Chemistry

Mondal, M., Radeva, N., Fanlo-Virgos, H., Otto, S., Klebe, G. & Hirsch, A. K. H., 1-Aug-2016, In : Angewandte Chemie - International Edition. 55, 32, p. 9422-9426 5 p.

Research output: Contribution to journalArticleAcademicpeer-review

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.

Original languageEnglish
Pages (from-to)9422-9426
Number of pages5
JournalAngewandte Chemie - International Edition
Issue number32
Publication statusPublished - 1-Aug-2016


  • dynamic combinatorial chemistry, fragment-based drug design, inhibitors, proteases, X-ray diffraction, X-RAY, CATALYTIC MECHANISM, COVALENT CHEMISTRY, BINDING FRAGMENTS, DISCOVERY, IDENTIFICATION, NEUTRON, NMR, PROTEINASES, DIFFRACTION

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