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Structure-based design of inhibitors of the aspartic protease endothiapepsin by exploiting dynamic combinatorial chemistry

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National Hellenic Research Foundation (NHRF)   

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Structure-based design of inhibitors of the aspartic protease endothiapepsin by exploiting dynamic combinatorial chemistry
Park A.
Radeva N.
Hirsch A.K.H.
Klebe G.
Potamitis C.
Mondal M.
Köster H.
Ζερβού, Μαρία
Άρθρο σε επιστημονικό περιοδικό
2014
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.
Φαρμακευτική χημεία (EL)
Pharmaceutical chemistry (EN)
X-ray diffraction (EN)
dynamic combinatorial chemistry (EN)
enzyme inhibitors (EN)
STD NMR spectroscopy (EN)
structure-based design (EN)
English
Wiley-VCH Verlag
Angewandte Chemie - International Edition
© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim. (EN)
National Hellenic Research Foundation (NHRF)
Helios - Repository of the National Hellenic Research Foundation (NHRF)



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