3FCQ

Thermolysin inhibition

3FCQ の概要

• エントリーDOI: 10.2210/pdb3fcq/pdb
• 関連するPDBエントリー: 3F28 3F2P 8TLN
• 分子名称: Thermolysin, ZINC ION, CALCIUM ION, ... (5 entities in total)
• 機能のキーワード: protein fragment complex, calcium, hydrolase, metal-binding, metalloprotease, protease, secreted, zinc, zymogen
• 由来する生物種: Bacillus thermoproteolyticus
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 34782.21

構造登録者

Steuber, H.,Englert, L.,Silber, K.,Heine, A.,Klebe, G. (登録日: 2008-11-22, 公開日: 2009-12-08, 最終更新日: 2023-09-06)

主引用文献

Englert, L.,Silber, K.,Steuber, H.,Brass, S.,Over, B.,Gerber, H.D.,Heine, A.,Diederich, W.E.,Klebe, G.
Fragment-Based Lead Discovery: Screening and Optimizing Fragments for Thermolysin Inhibition.
Chemmedchem, 5:930-940, 2010

PubMed Abstract: Fragment-based drug discovery has gained a foothold in today's lead identification processes. We present the application of in silico fragment-based screening for the discovery of novel lead compounds for the metalloendoproteinase thermolysin. We have chosen thermolysin to validate our screening approach as it is a well-studied enzyme and serves as a model system for other proteases. A protein-targeted virtual library was designed and screening was carried out using the program AutoDock. Two fragment hits could be identified. For one of them, the crystal structure in complex with thermolysin is presented. This compound was selected for structure-based optimization of binding affinity and improvement of ligand efficiency, while concomitantly keeping the fragment-like properties of the initial hit. Redesigning the zinc coordination group revealed a novel class of fragments possessing K(i) values as low as 128 microM, thus they provide a good starting point for further hit evolution in a tailored lead design.

PubMed: 20394106
DOI: 10.1002/cmdc.201000084

実験手法

X-RAY DIFFRACTION (1.75 Å)