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Structure-Based Design of Inhibitors of the Aspartic Protease Endothiapepsin by Exploiting Dynamic Combinatorial Chemistry

Mondal, Milon ; Radeva, Nedyalka ; Köster, Helene ; Park, Ahyoung ; Potamitis, Constantinos ; Zervou, Maria ; Klebe, Gerhard ; Hirsch, Anna K. H.

Angewandte Chemie (International ed.), 2014-03, Vol.53 (12), p.3259-3263 [Periódico revisado por pares]

Weinheim: WILEY-VCH Verlag

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  • Título:
    Structure-Based Design of Inhibitors of the Aspartic Protease Endothiapepsin by Exploiting Dynamic Combinatorial Chemistry
  • Autor: Mondal, Milon ; Radeva, Nedyalka ; Köster, Helene ; Park, Ahyoung ; Potamitis, Constantinos ; Zervou, Maria ; Klebe, Gerhard ; Hirsch, Anna K. H.
  • Assuntos: Aspartic Acid Endopeptidases - chemical synthesis ; Aspartic Acid Endopeptidases - chemistry ; Binders ; Combinatorial analysis ; Combinatorial chemistry ; Combinatorial Chemistry Techniques - instrumentation ; Combinatorial Chemistry Techniques - methods ; Drug Design ; dynamic combinatorial chemistry ; Dynamics ; enzyme inhibitors ; Inhibitors ; Libraries ; Magnetic Resonance Spectroscopy ; Models, Molecular ; Molecular Structure ; Optimization ; Protease ; STD NMR spectroscopy ; Structure-Activity Relationship ; structure-based design ; X-Ray Diffraction
  • É parte de: Angewandte Chemie (International ed.), 2014-03, Vol.53 (12), p.3259-3263
  • Notas: Dutch Ministry of Education, Culture, Science - No. 024.001.035
    We thank Pieter van der Meulen for useful suggestions and discussions about STD NMR spectroscopy. Funding was granted by the Netherlands Organisation for Scientific Research (NWO-CW, VENI grant to A.K.H.H.), by the Dutch Ministry of Education, Culture, Science (Gravity program 024.001.035) and European Union's Seventh Framework Programme (FP7-REGPOT-2009-1) under grant agreement no. 245866 (to C.P. and M.Z.), and by the ERC advanced grant no. 268145 DrugProfilBind kindly provided by the EU.
    istex:7B090747F81EDC1C7785FC22F4EAD918951E90BD
    Netherlands Organisation for Scientific Research
    ERC - No. 268145
    ArticleID:ANIE201309682
    European Union - No. 245866
    ark:/67375/WNG-WJ6FG8PL-8
    We thank Pieter van der Meulen for useful suggestions and discussions about STD NMR spectroscopy. Funding was granted by the Netherlands Organisation for Scientific Research (NWO‐CW, VENI grant to A.K.H.H.), by the Dutch Ministry of Education, Culture, Science (Gravity program 024.001.035) and European Union’s Seventh Framework Programme (FP7‐REGPOT‐2009‐1) under grant agreement no. 245866 (to C.P. and M.Z.), and by the ERC advanced grant no. 268145 DrugProfilBind kindly provided by the EU.
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    SourceType-Scholarly Journals-1
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  • Descrição: 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. The dynamic duo: The combination of de novo structure‐based design and dynamic combinatorial chemistry has been applied to the identification of novel acylhydrazone‐based inhibitors for the aspartic protease endothiapepsin. 1H‐STD‐NMR spectroscopy has been used to identify the binders from the dynamic combinatorial libraries. Proposed binding modes of the most potent inhibitors have been confirmed by X‐ray crystallography.
  • Editor: Weinheim: WILEY-VCH Verlag
  • Idioma: Inglês
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  • Realização: ABCD-USP USP   Logos de Redes Sociais: Freepik

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