title: Structure-based design of inhibitors of the aspartic protease endothiapepsin by exploiting dynamic combinatorial chemistry.
abstract: Structure-based design (SBD) can be used for the design and/or optimization of new inhibitors for a biological target. Whereas de novo SBD is rarely used, most reports on SBD are dealing with the optimization of an initial hit. Dynamic combinatorial chemistry (DCC) has emerged as a powerful strategy to identify bioactive ligands given that it enables the target to direct the synthesis of its strongest binder. We have designed a library of potential inhibitors (acylhydrazones) generated from five aldehydes and five hydrazides and used DCC to identify the best binder(s). After addition of the aspartic protease endothiapepsin, we characterized the protein-bound library member(s) by saturation-transfer difference NMR spectroscopy. Cocrystallization experiments validated the predicted binding mode of the two most potent inhibitors, thus demonstrating that the combination of de novo SBD and DCC constitutes an efficient starting point for hit identification and optimization.
authors: Stratingh Institute for Chemistry, University of Groningen, Nijenborgh 7, 9747 AG Groningen (The Netherlands) http://www.rug.nl/research/bio-organic-chemistry/hirsch/
authors: Milon
authors: M
authors: Mondal
authors: Nedyalka
authors: N
authors: Radeva
authors: Helene
authors: H
authors: Köster
authors: Ahyoung
authors: A
authors: Park
authors: Constantinos
authors: C
authors: Potamitis
authors: Maria
authors: M
authors: Zervou
authors: Gerhard
authors: G
authors: Klebe
authors: Anna K H
authors: AK
authors: Hirsch
mesh_terms: D016282:Aspartic Acid Endopeptidases / Q000138:chemical synthesis* / Q000737:chemistry*; D020650:Combinatorial Chemistry Techniques / Q000295:instrumentation* / Q000379:methods; D015195:Drug Design; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D014961:X-Ray Diffraction
chemical_list: D016282:Aspartic Acid Endopeptidases; C042466:Endothia aspartic proteinase
keywords: STD NMR spectroscopy; X-ray diffraction; dynamic combinatorial chemistry; enzyme inhibitors; structure-based design