Fragment‐Based Drug Design Facilitated by Protein‐Templated Click Chemistry: Fragment Linking and Optimization of Inhibitors of the Aspartic Protease Endothiapepsin. Issue 42 (7th September 2016)

• Record Type: Journal Article
• Authors: Mondal, Milon; Unver, M. Yagiz; Pal, Asish; Bakker, Matthijs; Berrier, Stephan P.; Hirsch, Anna K. H.
• Is Part Of: Chemistry. Volume 22:Issue 42(2016)
• Page Start: 14826
• Page End: 14830
• Publication Date: 2016-09-07
• Subjects: click chemistry -- drug design -- enzymes -- inhibitors -- liquid chromatography; Chemistry -- Periodicals; 540
• DOI: 10.1002/chem.201603001
• Languages: English
• ISSNs: 0947-6539

Abstract

Abstract: 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. Abstract : 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 highly sensitive UPLC‐TOF‐SIM method has been used to identify the triazole binders templated by the protein. The best binder inhibits endothiapepsin with an IC50 value of 43 μm .