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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
Author(s) -
Mondal Milon,
Unver M. Yagiz,
Pal Asish,
Bakker Matthijs,
Berrier Stephan P.,
Hirsch Anna K. H.
Publication year - 2016
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.201603001
Subject(s) - fragment (logic) , click chemistry , protease , combinatorial chemistry , chemistry , computational biology , drug , drug discovery , computer science , biochemistry , enzyme , biology , pharmacology , programming language
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 IC 50 value of 43 μ m , represents the first example of triazole‐based inhibitors of endothiapepsin. Our strategy could find application on a whole range of drug targets.