6zuu: Difference between revisions
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New page: '''Unreleased structure''' The entry 6zuu is ON HOLD Authors: Schafer, M. Description: Crystal structure of Thrombin in complex with compound30 Category: Unreleased Structures [[Ca... |
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==Crystal structure of Thrombin in complex with compound30== | |||
<StructureSection load='6zuu' size='340' side='right'caption='[[6zuu]], [[Resolution|resolution]] 1.94Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[6zuu]] is a 3 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=6ZUU OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6ZUU 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]] 1.94Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=QQN:[2-[(3-chlorophenyl)methylamino]-4-methoxy-1,3-benzoxazol-6-yl]-[(3~{R},4~{R})-3-methyl-4-oxidanyl-piperidin-1-yl]methanone'>QQN</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=6zuu FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6zuu OCA], [https://pdbe.org/6zuu PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6zuu RCSB], [https://www.ebi.ac.uk/pdbsum/6zuu PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6zuu ProSAT]</span></td></tr> | |||
</table> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Despite extensive research on small molecule thrombin inhibitors for oral application in the past decades, only a single double prodrug with very modest oral bioavailability has reached human therapy as a marketed drug. We have undertaken major efforts to identify neutral, non-prodrug inhibitors. Using a holistic analysis of all available internal data, we were able to build computational models and apply these for the selection of a lead series with the highest possibility of achieving oral bioavailability. In our design, we relied on protein structure knowledge to address potency and identified a small window of favorable physicochemical properties to balance absorption and metabolic stability. Protein structure information on the pregnane X receptor helped in overcoming a persistent cytochrome P450 3A4 induction problem. The selected compound series was optimized to a highly potent, neutral, non-prodrug thrombin inhibitor by designing, synthesizing, and testing derivatives. The resulting optimized compound, BAY1217224, has reached first clinical trials, which have confirmed the desired pharmacokinetic properties. | |||
Design, Synthesis, and Pharmacological Characterization of a Neutral, Non-Prodrug Thrombin Inhibitor with Good Oral Pharmacokinetics.,Hillisch A, Gericke KM, Allerheiligen S, Roehrig S, Schaefer M, Tersteegen A, Schulz S, Lienau P, Gnoth M, Puetter V, Hillig RC, Heitmeier S J Med Chem. 2020 Oct 27. doi: 10.1021/acs.jmedchem.0c01035. PMID:33108181<ref>PMID:33108181</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
[[Category: Schafer | <div class="pdbe-citations 6zuu" 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: Large Structures]] | |||
[[Category: Schafer M]] | |||
Latest revision as of 08:32, 17 October 2024
Crystal structure of Thrombin in complex with compound30
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