2c90: Difference between revisions
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==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, = 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. | 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. | ||
==Disease== | |||
Known diseases associated with this structure: Dysprothrombinemia OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=176930 176930]], Hyperprothrombinemia OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=176930 176930]], Hypoprothrombinemia OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=176930 176930]] | |||
==About this Structure== | ==About this Structure== | ||
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[[Category: zymogen]] | [[Category: zymogen]] | ||
''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Nov | ''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Nov 12 21:12:51 2007'' | ||