3FCQ

Thermolysin inhibition

Summary for 3FCQ

• Entry DOI: 10.2210/pdb3fcq/pdb
• Related: 3F28 3F2P 8TLN
• Descriptor: Thermolysin, ZINC ION, CALCIUM ION, ... (5 entities in total)
• Functional Keywords: protein fragment complex, calcium, hydrolase, metal-binding, metalloprotease, protease, secreted, zinc, zymogen
• Biological source: Bacillus thermoproteolyticus
• Total number of polymer chains: 1
• Total formula weight: 34782.21

Authors

Steuber, H.,Englert, L.,Silber, K.,Heine, A.,Klebe, G. (deposition date: 2008-11-22, release date: 2009-12-08, Last modification date: 2023-09-06)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (1.75 Å)