1ta6
From Proteopedia
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|PDB= 1ta6 |SIZE=350|CAPTION= <scene name='initialview01'>1ta6</scene>, resolution 1.90Å | |PDB= 1ta6 |SIZE=350|CAPTION= <scene name='initialview01'>1ta6</scene>, resolution 1.90Å | ||
|SITE= | |SITE= | ||
| - | |LIGAND= <scene name='pdbligand=177:1-[2-AMINO-2-CYCLOHEXYL-ACETYL]-PYRROLIDINE-3-CARBOXYLIC ACID 5-CHLORO-2-(2-ETHYLCARBAMOYL-ETHOXY)-BENZYLAMIDE'>177</scene> | + | |LIGAND= <scene name='pdbligand=177:1-[2-AMINO-2-CYCLOHEXYL-ACETYL]-PYRROLIDINE-3-CARBOXYLIC+ACID+5-CHLORO-2-(2-ETHYLCARBAMOYL-ETHOXY)-BENZYLAMIDE'>177</scene>, <scene name='pdbligand=TYS:SULFONATED+TYROSINE'>TYS</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=[[1sl3|1SL3]], [[1ta2|1TA2]] | ||
| + | |RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1ta6 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1ta6 OCA], [http://www.ebi.ac.uk/pdbsum/1ta6 PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=1ta6 RCSB]</span> | ||
}} | }} | ||
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==Overview== | ==Overview== | ||
As part of an ongoing effort to prepare therapeutically useful orally active thrombin inhibitors, we have synthesized a series of compounds that utilize nonbasic groups in the P1 position. The work is based on our previously reported lead structure, compound 1, which was discovered via a resin-based approach to varying P1. By minimizing the size and lipophilicity of the P3 group and by incorporating hydrogen-bonding groups on the N-terminus or on the 2-position of the P1 aromatic ring, we have prepared a number of derivatives in this series that exhibit subnanomolar enzyme potency combined with good in vivo antithrombotic and bioavailability profiles. The oxyacetic amide compound 14b exhibited the best overall profile of in vitro and in vivo activity, and crystallographic studies indicate a unique mode of binding in the thrombin active site. | As part of an ongoing effort to prepare therapeutically useful orally active thrombin inhibitors, we have synthesized a series of compounds that utilize nonbasic groups in the P1 position. The work is based on our previously reported lead structure, compound 1, which was discovered via a resin-based approach to varying P1. By minimizing the size and lipophilicity of the P3 group and by incorporating hydrogen-bonding groups on the N-terminus or on the 2-position of the P1 aromatic ring, we have prepared a number of derivatives in this series that exhibit subnanomolar enzyme potency combined with good in vivo antithrombotic and bioavailability profiles. The oxyacetic amide compound 14b exhibited the best overall profile of in vitro and in vivo activity, and crystallographic studies indicate a unique mode of binding in the thrombin active site. | ||
| - | |||
| - | ==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: Vacca, J P.]] | [[Category: Vacca, J P.]] | ||
[[Category: Yan, Y.]] | [[Category: Yan, Y.]] | ||
| - | [[Category: 177]] | ||
[[Category: thrombin inhibitor complex]] | [[Category: thrombin inhibitor complex]] | ||
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun Mar 30 23:53:29 2008'' |
Revision as of 20:53, 30 March 2008
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| , resolution 1.90Å | |||||||
|---|---|---|---|---|---|---|---|
| Ligands: | , | ||||||
| Activity: | Thrombin, with EC number 3.4.21.5 | ||||||
| Related: | 1SL3, 1TA2
| ||||||
| Resources: | FirstGlance, OCA, PDBsum, RCSB | ||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||
Crystal structure of thrombin in complex with compound 14b
Overview
As part of an ongoing effort to prepare therapeutically useful orally active thrombin inhibitors, we have synthesized a series of compounds that utilize nonbasic groups in the P1 position. The work is based on our previously reported lead structure, compound 1, which was discovered via a resin-based approach to varying P1. By minimizing the size and lipophilicity of the P3 group and by incorporating hydrogen-bonding groups on the N-terminus or on the 2-position of the P1 aromatic ring, we have prepared a number of derivatives in this series that exhibit subnanomolar enzyme potency combined with good in vivo antithrombotic and bioavailability profiles. The oxyacetic amide compound 14b exhibited the best overall profile of in vitro and in vivo activity, and crystallographic studies indicate a unique mode of binding in the thrombin active site.
About this Structure
1TA6 is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.
Reference
Design and synthesis of a series of potent and orally bioavailable noncovalent thrombin inhibitors that utilize nonbasic groups in the P1 position., Tucker TJ, Brady SF, Lumma WC, Lewis SD, Gardell SJ, Naylor-Olsen AM, Yan Y, Sisko JT, Stauffer KJ, Lucas BJ, Lynch JJ, Cook JJ, Stranieri MT, Holahan MA, Lyle EA, Baskin EP, Chen IW, Dancheck KB, Krueger JA, Cooper CM, Vacca JP, J Med Chem. 1998 Aug 13;41(17):3210-9. PMID:9703466
Page seeded by OCA on Sun Mar 30 23:53:29 2008
Categories: Homo sapiens | Single protein | Thrombin | Baskin, E P. | Brady, S F. | Chen, I W. | Cook, J J. | Cooper, C M. | Dancheck, K B. | Gardel, S J. | Holahan, M A. | Krueger, J A. | Lewis, S D. | Lucas, B Y. | Lumma, W C. | Lyle, E A. | Lynch, J J. | Naylor-Olsen, A M. | Sisko, J T. | Stauffer, K J. | Stranieri, M T. | Tucker, T J. | Vacca, J P. | Yan, Y. | Thrombin inhibitor complex
