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< | ==Crystal structure of thrombin in complex with compound 14b== | ||
<StructureSection load='1ta6' size='340' side='right'caption='[[1ta6]], [[Resolution|resolution]] 1.90Å' scene=''> | |||
You may | == Structural highlights == | ||
<table><tr><td colspan='2'>[[1ta6]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Hirudo_medicinalis Hirudo medicinalis] and [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1TA6 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1TA6 FirstGlance]. <br> | |||
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.9Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><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:O-SULFO-L-TYROSINE'>TYS</scene></td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=1ta6 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1ta6 OCA], [https://pdbe.org/1ta6 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1ta6 RCSB], [https://www.ebi.ac.uk/pdbsum/1ta6 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1ta6 ProSAT]</span></td></tr> | |||
</table> | |||
== Evolutionary Conservation == | |||
[[Image:Consurf_key_small.gif|200px|right]] | |||
Check<jmol> | |||
<jmolCheckbox> | |||
<scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/ta/1ta6_consurf.spt"</scriptWhenChecked> | |||
<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview03.spt</scriptWhenUnchecked> | |||
<text>to colour the structure by Evolutionary Conservation</text> | |||
</jmolCheckbox> | |||
</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=1ta6 ConSurf]. | |||
<div style="clear:both"></div> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
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. | |||
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<ref>PMID:9703466</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 1ta6" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[Hirudin 3D structures|Hirudin 3D structures]] | |||
*[[Thrombin 3D Structures|Thrombin 3D Structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
== | </StructureSection> | ||
[[Category: Hirudo medicinalis]] | |||
== | |||
[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: | [[Category: Large Structures]] | ||
[[Category: Baskin EP]] | |||
[[Category: Baskin | [[Category: Brady SF]] | ||
[[Category: Brady | [[Category: Chen I-W]] | ||
[[Category: Chen | [[Category: Cook JJ]] | ||
[[Category: Cook | [[Category: Cooper CM]] | ||
[[Category: Cooper | [[Category: Dancheck KB]] | ||
[[Category: Dancheck | [[Category: Gardel SJ]] | ||
[[Category: Gardel | [[Category: Holahan MA]] | ||
[[Category: Holahan | [[Category: Krueger JA]] | ||
[[Category: Krueger | [[Category: Lewis SD]] | ||
[[Category: Lewis | [[Category: Lucas BY]] | ||
[[Category: Lucas | [[Category: Lumma WC]] | ||
[[Category: Lumma | [[Category: Lyle EA]] | ||
[[Category: Lyle | [[Category: Lynch JJ]] | ||
[[Category: Lynch | [[Category: Naylor-Olsen AM]] | ||
[[Category: Naylor-Olsen | [[Category: Sisko JT]] | ||
[[Category: Sisko | [[Category: Stauffer KJ]] | ||
[[Category: Stauffer | [[Category: Stranieri MT]] | ||
[[Category: Stranieri | [[Category: Tucker TJ]] | ||
[[Category: Tucker | [[Category: Vacca JP]] | ||
[[Category: Vacca | [[Category: Yan Y]] | ||
[[Category: Yan | |||
Latest revision as of 03:30, 21 November 2024
Crystal structure of thrombin in complex with compound 14bCrystal structure of thrombin in complex with compound 14b
Structural highlights
Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMedAs 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. 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[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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