2c8w: Difference between revisions
From Proteopedia
Jump to navigationJump to search
No edit summary |
No edit summary |
||
| Line 5: | Line 5: | ||
==Overview== | ==Overview== | ||
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, = ... | 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. | ||
==About this Structure== | ==About this Structure== | ||
2C8W is a | 2C8W is a [http://en.wikipedia.org/wiki/Protein_complex Protein complex] structure of sequences from [http://en.wikipedia.org/wiki/Hirudo_medicinalis Hirudo medicinalis] and [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with NA and C7M as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Thrombin Thrombin], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.21.5 3.4.21.5] Structure known Active Site: AC1. Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=2C8W OCA]. | ||
==Reference== | ==Reference== | ||
| Line 44: | Line 44: | ||
[[Category: zymogen]] | [[Category: zymogen]] | ||
''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on | ''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Nov 5 15:25:24 2007'' | ||
