2c93: 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: thrombin]] | [[Category: thrombin]] | ||
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Revision as of 22:06, 12 November 2007
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THROMBIN INHIBITORS
OverviewOverview
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.
DiseaseDisease
Known diseases associated with this structure: Dysprothrombinemia OMIM:[176930], Hyperprothrombinemia OMIM:[176930], Hypoprothrombinemia OMIM:[176930]
About this StructureAbout this Structure
2C93 is a Protein complex structure of sequences from Hirudo medicinalis and Homo sapiens with NA, DMS and C4M as ligands. Active as Thrombin, with EC number 3.4.21.5 Structure known Active Site: AC1. Full crystallographic information is available from OCA.
ReferenceReference
Application of fragment screening and fragment linking to the discovery of novel thrombin inhibitors., Howard N, Abell C, Blakemore W, Chessari G, Congreve M, Howard S, Jhoti H, Murray CW, Seavers LC, van Montfort RL, J Med Chem. 2006 Feb 23;49(4):1346-55. PMID:16480269
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Proteopedia Page Contributors and Editors (what is this?)Proteopedia Page Contributors and Editors (what is this?)
OCA- Pages with broken file links
- Hirudo medicinalis
- Homo sapiens
- Protein complex
- Thrombin
- Abell, C.
- Blakemore, W.
- Carr, R.
- Chessari, G.
- Congreve, M.
- Howard, N.
- Howard, S.
- Jhoti, H.
- Montfort, R.L.M.Van.
- Murray, C.W.
- Seavers, L.C.A.
- C4M
- DMS
- NA
- Blood coagulation
- Gamma-carboxyglutamic acid
- Glycoprotein
- Hydrolase
- Kringle
- Protease
- Serine protease