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4LHH

Endothiapepsin in complex with 2mM acylhydrazone inhibitor

Summary for 4LHH
Entry DOI10.2210/pdb4lhh/pdb
Related3T7P 4KUP 4LBT
DescriptorEndothiapepsin, (2S)-2-azanyl-3-(3H-indol-3-yl)-N-[(E)-(2,4,6-trimethylphenyl)methylideneamino]propanamide, GLYCEROL, ... (6 entities in total)
Functional Keywordshydrolase, aspartic protease, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
Biological sourceCryphonectria parasitica (Chesnut blight fungus)
Total number of polymer chains1
Total formula weight34883.16
Authors
Radeva, N.,Heine, A.,Klebe, G. (deposition date: 2013-07-01, release date: 2014-04-02, Last modification date: 2024-10-09)
Primary citationMondal, M.,Radeva, N.,Koster, H.,Park, A.,Potamitis, C.,Zervou, M.,Klebe, G.,Hirsch, A.K.
Structure-based design of inhibitors of the aspartic protease endothiapepsin by exploiting dynamic combinatorial chemistry.
Angew.Chem.Int.Ed.Engl., 53:3259-3263, 2014
Cited by
PubMed 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.
PubMed: 24532096
DOI: 10.1002/anie.201309682
PDB entries with the same primary citation
Experimental method
X-RAY DIFFRACTION (1.73 Å)
Structure validation

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数据于2024-11-06公开中

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