3WZ8

Endothiapepsin in complex with Gewald reaction-derived inhibitor (8)

3WZ8 の概要

• エントリーDOI: 10.2210/pdb3wz8/pdb
• 関連するPDBエントリー: 3WZ6 3WZ7
• 分子名称: Endothiapepsin, N-benzyl-4-phenyl-2-[(N-phenyl-beta-alanyl)amino]thiophene-3-carboxamide, DI(HYDROXYETHYL)ETHER, ... (5 entities in total)
• 機能のキーワード: aspartic protease, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• 由来する生物種: Cryphonectria parasitica (Chesnut blight fungus)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 34453.68

構造登録者

Kuhnert, M.,Steuber, H.,Diederich, W.E. (登録日: 2014-09-19, 公開日: 2015-08-05, 最終更新日: 2024-11-20)

主引用文献

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

実験手法

X-RAY DIFFRACTION (1.45 Å)