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

Milon Mondal, Nedyalka Radeva, Hugo Fanlo-Virgos, Sijbren Otto, Gerhard Klebe, Anna K. H. Hirsch*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

36 Citations (Scopus)
322 Downloads (Pure)

Abstract

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
Volume55
Issue number32
DOIs
Publication statusPublished - 1-Aug-2016

Keywords

  • 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

Cite this