2a2x
From Proteopedia
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|PDB= 2a2x |SIZE=350|CAPTION= <scene name='initialview01'>2a2x</scene>, resolution 2.440Å | |PDB= 2a2x |SIZE=350|CAPTION= <scene name='initialview01'>2a2x</scene>, resolution 2.440Å | ||
|SITE= | |SITE= | ||
| - | |LIGAND= <scene name='pdbligand=NA9:N-(CARBOXYMETHYL)-3-CYCLOHEXYL-D-ALANYL-N-({6-[AMINO(IMINO)METHYL]PYRIDIN-3-YL}METHYL)-N~2~-METHYL-L-ALANINAMIDE'>NA9</scene> | + | |LIGAND= <scene name='pdbligand=ALC:2-AMINO-3-CYCLOHEXYL-PROPIONIC+ACID'>ALC</scene>, <scene name='pdbligand=HYP:4-HYDROXYPROLINE'>HYP</scene>, <scene name='pdbligand=NA9:N-(CARBOXYMETHYL)-3-CYCLOHEXYL-D-ALANYL-N-({6-[AMINO(IMINO)METHYL]PYRIDIN-3-YL}METHYL)-N~2~-METHYL-L-ALANINAMIDE'>NA9</scene>, <scene name='pdbligand=SIN:SUCCINIC+ACID'>SIN</scene>, <scene name='pdbligand=SMF:4-SULFOMETHYL-L-PHENYLALANINE'>SMF</scene> |
| - | |ACTIVITY= [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] | + | |ACTIVITY= <span class='plainlinks'>[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] </span> |
|GENE= | |GENE= | ||
| + | |DOMAIN= | ||
| + | |RELATEDENTRY=[[2ank|2ANK]] | ||
| + | |RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2a2x FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2a2x OCA], [http://www.ebi.ac.uk/pdbsum/2a2x PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=2a2x RCSB]</span> | ||
}} | }} | ||
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==Overview== | ==Overview== | ||
Synthesis and SAR of orally active thrombin inhibitors of the d-Phe-Pro-Arg type with focus on the P2-moiety are described. The unexpected increase in in vitro potency, oral bioavailability, and in vivo activity of inhibitors with dehydroproline as P2-isostere is discussed. Over a period of 24h the antithrombin activity of the most active inhibitors with IC(50)s in the nanomolar range was determined in dogs demonstrating high thrombin inhibitory activity in plasma and an appropriate duration of action after oral administration. | Synthesis and SAR of orally active thrombin inhibitors of the d-Phe-Pro-Arg type with focus on the P2-moiety are described. The unexpected increase in in vitro potency, oral bioavailability, and in vivo activity of inhibitors with dehydroproline as P2-isostere is discussed. Over a period of 24h the antithrombin activity of the most active inhibitors with IC(50)s in the nanomolar range was determined in dogs demonstrating high thrombin inhibitory activity in plasma and an appropriate duration of action after oral administration. | ||
| - | |||
| - | ==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: Mack, H.]] | [[Category: Mack, H.]] | ||
[[Category: Seitz, W.]] | [[Category: Seitz, W.]] | ||
| - | [[Category: NA9]] | ||
[[Category: blood clotting]] | [[Category: blood clotting]] | ||
| - | [[Category: serine protease]] | + | [[Category: serine protease,]] |
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Mar 31 01:47:05 2008'' |
Revision as of 22:47, 30 March 2008
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| , resolution 2.440Å | |||||||
|---|---|---|---|---|---|---|---|
| Ligands: | , , , , | ||||||
| Activity: | Thrombin, with EC number 3.4.21.5 | ||||||
| Related: | 2ANK
| ||||||
| Resources: | FirstGlance, OCA, PDBsum, RCSB | ||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||
Orally Active Thrombin Inhibitors in Complex with Thrombin Inh12
Overview
Synthesis and SAR of orally active thrombin inhibitors of the d-Phe-Pro-Arg type with focus on the P2-moiety are described. The unexpected increase in in vitro potency, oral bioavailability, and in vivo activity of inhibitors with dehydroproline as P2-isostere is discussed. Over a period of 24h the antithrombin activity of the most active inhibitors with IC(50)s in the nanomolar range was determined in dogs demonstrating high thrombin inhibitory activity in plasma and an appropriate duration of action after oral administration.
About this Structure
2A2X is a Protein complex structure of sequences from Homo sapiens. Full crystallographic information is available from OCA.
Reference
Orally active thrombin inhibitors. Part 2: optimization of the P2-moiety., Lange UE, Baucke D, Hornberger W, Mack H, Seitz W, Hoffken HW, Bioorg Med Chem Lett. 2006 May 15;16(10):2648-53. Epub 2006 Feb 3. PMID:16460939
Page seeded by OCA on Mon Mar 31 01:47:05 2008
