5HCT

Endothiapepsin in complex with biacylhydrazone

Summary for 5HCT

• Entry DOI: 10.2210/pdb5hct/pdb
• Related: 3PGI
• Descriptor: Endothiapepsin, DIMETHYL SULFOXIDE, GLYCEROL, ... (8 entities in total)
• Functional Keywords: hydrolase, inhibition
• Biological source: Cryphonectria parasitica (Chesnut blight fungus)
• Total number of polymer chains: 1
• Total formula weight: 44483.03

Authors

Radeva, N.,Heine, A.,Klebe, G. (deposition date: 2016-01-04, release date: 2016-07-20, Last modification date: 2024-11-13)

Primary citation

Mondal, M.,Radeva, N.,Fanlo-Virgos, H.,Otto, S.,Klebe, G.,Hirsch, A.K.
Fragment Linking and Optimization of Inhibitors of the Aspartic Protease Endothiapepsin: Fragment-Based Drug Design Facilitated by Dynamic Combinatorial Chemistry.
Angew.Chem.Int.Ed.Engl., 55:9422-9426, 2016

PubMed Abstract: Fragment-based drug design (FBDD) affords active compounds for biological targets. While there are numerous reports on FBDD by fragment growing/optimization, fragment linking has rarely been reported. Dynamic combinatorial chemistry (DCC) has become a powerful hit-identification strategy for biological targets. We report the synergistic combination of fragment linking and DCC to identify inhibitors of the aspartic protease endothiapepsin. Based on X-ray crystal structures of endothiapepsin in complex with fragments, we designed a library of bis-acylhydrazones and used DCC to identify potent inhibitors. The most potent inhibitor exhibits an IC50 value of 54 nm, which represents a 240-fold improvement in potency compared to the parent hits. Subsequent X-ray crystallography validated the predicted binding mode, thus demonstrating the efficiency of the combination of fragment linking and DCC as a hit-identification strategy. This approach could be applied to a range of biological targets, and holds the potential to facilitate hit-to-lead optimization.

PubMed: 27400756
DOI: 10.1002/anie.201603074

Experimental method

X-RAY DIFFRACTION (1.36 Å)