3PSY

Endothiapepsin in complex with an inhibitor based on the Gewald reaction

Summary for 3PSY

• Entry DOI: 10.2210/pdb3psy/pdb
• Descriptor: Endothiapepsin, N-benzyl-2-({N-[2-(1H-indol-3-yl)ethyl]glycyl}amino)-4-phenylthiophene-3-carboxamide, DIMETHYL SULFOXIDE, ... (7 entities in total)
• Functional Keywords: hydrolase, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Cryphonectria parasitica (Chesnut blight fungus)
• Total number of polymer chains: 1
• Total formula weight: 34925.22

Authors

Koester, H.,Heine, A.,Klebe, G. (deposition date: 2010-12-02, release date: 2011-12-07, Last modification date: 2024-11-13)

Primary citation

Kuhnert, M.,Koster, H.,Bartholomaus, R.,Park, A.Y.,Shahim, A.,Heine, A.,Steuber, H.,Klebe, G.,Diederich, W.E.
Tracing binding modes in hit-to-lead optimization: chameleon-like poses of aspartic protease inhibitors.
Angew.Chem.Int.Ed.Engl., 54:2849-2853, 2015

PubMed Abstract: Successful lead optimization in structure-based drug discovery depends on the correct deduction and interpretation of the underlying structure-activity relationships (SAR) to facilitate efficient decision-making on the next candidates to be synthesized. Consequently, the question arises, how frequently a binding mode (re)-validation is required, to ensure not to be misled by invalid assumptions on the binding geometry. We present an example in which minor chemical modifications within one inhibitor series lead to surprisingly different binding modes. X-ray structure determination of eight inhibitors derived from one core scaffold resulted in four different binding modes in the aspartic protease endothiapepsin, a well-established surrogate for e.g. renin and β-secretase. In addition, we suggest an empirical metrics that might serve as an indicator during lead optimization to qualify compounds as candidates for structural revalidation.

PubMed: 25630461
DOI: 10.1002/anie.201411206

Experimental method

X-RAY DIFFRACTION (1.43 Å)