2C8X
thrombin inhibitors
Summary for 2C8X
| Entry DOI | 10.2210/pdb2c8x/pdb |
| Related | 2C8W 2C8Y 2C8Z 2C90 2C93 |
| Descriptor | THROMBIN LIGHT CHAIN, THROMBIN HEAVY CHAIN, HIRUDIN VARIANT-2, ... (7 entities in total) |
| Functional Keywords | protease, blood coagulation, thrombin, gamma-carboxyglutamic acid, glycoprotein, kringle, serine protease, 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 | 36121.67 |
| 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: 2024-10-16) |
| 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 Cited by 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: 16480269DOI: 10.1021/JM050850V PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.17 Å) |
Structure validation
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