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Fragment-Based Drug Design Facilitated by Protein-Templated Click Chemistry: Fragment Linking and -Optimization of Inhibitors of the Aspartic Protease Endothiapepsin

Mondal, M., Unver, M. Y., Pal, A., Bakker, M., Berrier, S. R. & Hirsch, A. K. H., Oct-2016, In : Chemistry. 22, 42, p. 14826-14830 5 p.

Research output: Contribution to journalArticleAcademicpeer-review

  • Milon Mondal
  • M. Yagiz Unver
  • Asish Pal
  • Matthijs Bakker
  • Stephan R. Berrier
  • Anna K H Hirsch

There is an urgent need for the development of efficient methodologies that accelerate drug discovery. We demonstrate that the strategic combination of fragment linking/optimization and protein-templated click chemistry is an efficient and powerful method that accelerates the hit-identification process for the aspartic protease endothiapepsin. The best binder, which inhibits endothiapepsin with an IC50 value of 43 μm, represents the first example of triazole-based inhibitors of endothiapepsin. Our strategy could find application on a whole range of drug targets.

Original languageEnglish
Pages (from-to)14826-14830
Number of pages5
JournalChemistry
Volume22
Issue number42
Publication statusPublished - Oct-2016

    Keywords

  • click chemistry, drug design, enzymes, inhibitors, liquid chromatography, DYNAMIC COMBINATORIAL CHEMISTRY, HYDE SCORING FUNCTION, LEAD DISCOVERY, X-RAY, CATALYTIC MECHANISM, HOT-SPOTS, POTENT, NMR, SAR, NEUTRON

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