4dmx: Difference between revisions
m Protected "4dmx" [edit=sysop:move=sysop] |
No edit summary |
||
| (9 intermediate revisions by the same user not shown) | |||
| Line 1: | Line 1: | ||
==Cathepsin K inhibitor== | |||
<StructureSection load='4dmx' size='340' side='right'caption='[[4dmx]], [[Resolution|resolution]] 1.70Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[4dmx]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4DMX OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4DMX 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]] 1.7Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=0LB:(1R,2R)-N-(1-CYANOCYCLOPROPYL)-2-{[4-(4-FLUOROPHENYL)PIPERAZIN-1-YL]CARBONYL}CYCLOHEXANECARBOXAMIDE'>0LB</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</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=4dmx FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4dmx OCA], [https://pdbe.org/4dmx PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4dmx RCSB], [https://www.ebi.ac.uk/pdbsum/4dmx PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4dmx ProSAT]</span></td></tr> | |||
</table> | |||
== Disease == | |||
[https://www.uniprot.org/uniprot/CATK_HUMAN CATK_HUMAN] Defects in CTSK are the cause of pycnodysostosis (PKND) [MIM:[https://omim.org/entry/265800 265800]. PKND is an autosomal recessive osteochondrodysplasia characterized by osteosclerosis and short stature.<ref>PMID:8703060</ref> <ref>PMID:9529353</ref> <ref>PMID:10491211</ref> <ref>PMID:10878663</ref> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/CATK_HUMAN CATK_HUMAN] Closely involved in osteoclastic bone resorption and may participate partially in the disorder of bone remodeling. Displays potent endoprotease activity against fibrinogen at acid pH. May play an important role in extracellular matrix degradation. | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Directed screening of nitrile compounds revealed 3 as a highly potent cathepsin K inhibitor but with cathepsin S activity and very poor stability to microsomes. Synthesis of compounds with reduced molecular complexity, such as 7, revealed key SAR and demonstrated that baseline physical properties and in-vitro stability were in fact excellent for this series. The tricycle carboline P3 unit was discovered by hypothesis based design using existing structural information. Optimisation using small substituents, knowledge from matched molecular pairs and control of lipophilicity yielded compounds very close to the desired profile, of which 34 (AZD4996) was selected on the basis of pharmacokinetic profile. | |||
(1R,2R)-N-(1-cyanocyclopropyl)-2-(6-methoxy-1,3,4,5-tetrahydropyrido[4,3-b]indole -2-carbonyl)cyclohexanecarboxamide (AZD4996): A potent and highly selective Cathepsin K inhibitor for the treatment of osteoarthritis.,Dossetter A, Beeley H, Bowyer J, Cook CR, Crawford JJ, Finlayson JE, Heron NM, Heyes C, Highton AJ, Hudson JA, Jestel A, Kenny PW, Krapp S, Martin S, Macfaul PA, McGuire TM, Morentin-Gutierrez P, Morley AD, Morris JJ, Page KM, Rosenbrier-Ribeiro L, Sawney H, Steinbacher S, Smith C, Vickers M J Med Chem. 2012 Jun 28. PMID:22742641<ref>PMID:22742641</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 4dmx" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[Cathepsin 3D structures|Cathepsin 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Homo sapiens]] | |||
[[Category: Large Structures]] | |||
[[Category: Beeley H]] | |||
[[Category: Bowyer J]] | |||
[[Category: Cook CR]] | |||
[[Category: Crawford JJ]] | |||
[[Category: Dossetter AG]] | |||
[[Category: Finlayson JE]] | |||
[[Category: Gutierrez PM]] | |||
[[Category: Heron NM]] | |||
[[Category: Heyes C]] | |||
[[Category: Highton AJ]] | |||
[[Category: Hudson JA]] | |||
[[Category: Jestel A]] | |||
[[Category: Kenny PW]] | |||
[[Category: Krapp S]] | |||
[[Category: MacFaul PA]] | |||
[[Category: Martin S]] | |||
[[Category: McGuire TM]] | |||
[[Category: Morley AD]] | |||
[[Category: Morris JJ]] | |||
[[Category: Page KM]] | |||
[[Category: Rosenbrier Ribeiro L]] | |||
[[Category: Sawney H]] | |||
[[Category: Smith C]] | |||
[[Category: Steinbacher S]] | |||
[[Category: Vickers M]] | |||