2C8W

thrombin inhibitors

Summary for 2C8W

• Entry DOI: 10.2210/pdb2c8w/pdb
• Related: 2C8X 2C8Y 2C8Z 2C90 2C93
• Descriptor: THROMBIN LIGHT CHAIN, THROMBIN HEAVY CHAIN, HIRUDIN VARIANT-2, ... (6 entities in total)
• Functional Keywords: protease, blood coagulation, thrombin, acute phase, disease mutation, gamma-carboxyglutamic acid, glycoprotein, kringle, plasma, serine protease, zymogen, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: HOMO SAPIENS (HUMAN); More
• Cellular location: Secreted, extracellular space: P00734 P00734; Secreted: P09945
• Total number of polymer chains: 3
• Total formula weight: 35994.38

Authors

Howard, N.,Abell, C.,Blakemore, W.,Carr, R.,Chessari, G.,Congreve, M.,Howard, S.,Jhoti, H.,Murray, C.W.,Seavers, L.C.A.,van Montfort, R.L.M. (deposition date: 2005-12-08, release date: 2006-07-04, Last modification date: 2024-11-13)

Primary citation

Howard, N.,Abell, C.,Blakemore, W.,Chessari, G.,Congreve, M.,Howard, S.,Jhoti, H.,Murray, C.W.,Seavers, L.C.A.,Van Montfort, R.L.M.
Application of Fragment Screening and Fragment Linking to the Discovery of Novel Thrombin Inhibitors
J.Med.Chem., 49:1346-, 2006

PubMed Abstract: The screening of fragments is an alternative approach to high-throughput screening for the identification of leads for therapeutic targets. Fragment hits have been discovered using X-ray crystallographic screening of protein crystals of the serine protease enzyme thrombin. The fragment library was designed to avoid any well-precedented, strongly basic functionality. Screening hits included a novel ligand (3), which binds exclusively to the S2-S4 pocket, in addition to smaller fragments which bind to the S1 pocket. The structure of these protein-ligand complexes are presented. A chemistry strategy to link two such fragments together and to synthesize larger drug-sized compounds resulted in the efficient identification of hybrid inhibitors with nanomolar potency (e.g., 7, IC50 = 3.7 nM). These potent ligands occupy the same area of the active site as previously described peptidic inhibitors, while having very different chemical architecture.

PubMed: 16480269
DOI: 10.1021/JM050850V

Experimental method

X-RAY DIFFRACTION (1.96 Å)