Fragment-Based Drug Design Facilitated by Protein-Templated Click Chemistry: Fragment Linking and Optimization of Inhibitors of the Aspartic Protease Endothiapepsin.
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 IC50value 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.
Stratingh Institute for Chemistry, University of Groningen, Nijenborgh 7, 9747 AG, Groningen, The Netherlands.
Milon
http://orcid.org/0000-0002-1613-7269
M
Mondal
Stratingh Institute for Chemistry, University of Groningen, Nijenborgh 7, 9747 AG, Groningen, The Netherlands.
M Yagiz
http://orcid.org/0000-0002-9797-7832
MY
Unver
Institute of Nano Science and Technology, Sector 64, Mohali, Punjab, 160062, India.
Asish
A
Pal
Stratingh Institute for Chemistry, University of Groningen, Nijenborgh 7, 9747 AG, Groningen, The Netherlands.
Matthijs
M
Bakker
Stratingh Institute for Chemistry, University of Groningen, Nijenborgh 7, 9747 AG, Groningen, The Netherlands.
Stephan P
SP
Berrier
Stratingh Institute for Chemistry, University of Groningen, Nijenborgh 7, 9747 AG, Groningen, The Netherlands. a.k.h.hirsch@rug.nl.
Anna K H
http://orcid.org/0000-0001-8734-4663
AK
Hirsch
D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D057930:Click Chemistry; D015195:Drug Design; D008958:Models, Molecular
D016282:Aspartic Acid Endopeptidases; C042466:Endothia aspartic proteinase
click chemistry; drug design; enzymes; inhibitors; liquid chromatography