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PDBsum entry 4lhh
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Hydrolase/hydrolase inhibitor
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PDB id
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4lhh
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References listed in PDB file
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Key reference
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Title
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Structure-Based design of inhibitors of the aspartic protease endothiapepsin by exploiting dynamic combinatorial chemistry.
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Authors
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M.Mondal,
N.Radeva,
H.Köster,
A.Park,
C.Potamitis,
M.Zervou,
G.Klebe,
A.K.Hirsch.
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Ref.
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Angew Chem Int Ed Engl, 2014,
53,
3259-3263.
[DOI no: ]
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PubMed id
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Abstract
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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.
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