4z0k

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(New page: '''Unreleased structure''' The entry 4z0k is ON HOLD Authors: Hruza, A., Reichert, P. Description: Rapid development of two Factor IXa inhibitors from Hit to Lead [[Category: Unrelease...)
Current revision (08:10, 27 September 2023) (edit) (undo)
 
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'''Unreleased structure'''
 
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The entry 4z0k is ON HOLD
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==Rapid development of two Factor IXa inhibitors from Hit to Lead==
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<StructureSection load='4z0k' size='340' side='right'caption='[[4z0k]], [[Resolution|resolution]] 1.41&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[4z0k]] is a 2 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=4Z0K OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4Z0K FirstGlance]. <br>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.41&#8491;</td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=4LN:N-[(2R)-10-HYDROXY-2,7-DIMETHYL-1,2,3,4-TETRAHYDROPYRIDO[1,2-B]INDAZOL-2-YL]-4-(4H-1,2,4-TRIAZOL-4-YL)BENZAMIDE'>4LN</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=NHE:2-[N-CYCLOHEXYLAMINO]ETHANE+SULFONIC+ACID'>NHE</scene></td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4z0k FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4z0k OCA], [https://pdbe.org/4z0k PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4z0k RCSB], [https://www.ebi.ac.uk/pdbsum/4z0k PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4z0k ProSAT]</span></td></tr>
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</table>
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== Disease ==
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[https://www.uniprot.org/uniprot/FA9_HUMAN FA9_HUMAN] Defects in F9 are the cause of recessive X-linked hemophilia B (HEMB) [MIM:[https://omim.org/entry/306900 306900]; also known as Christmas disease.<ref>PMID:8295821</ref> <ref>PMID:2592373</ref> <ref>PMID:2743975</ref> <ref>PMID:6603618</ref> <ref>PMID:3009023</ref> <ref>PMID:3790720</ref> <ref>PMID:3401602</ref> <ref>PMID:3243764</ref> <ref>PMID:2713493</ref> <ref>PMID:2714791</ref> <ref>PMID:2773937</ref> <ref>PMID:2775660</ref> <ref>PMID:2753873</ref> <ref>PMID:2738071</ref> <ref>PMID:2472424</ref> <ref>PMID:2339358</ref> <ref>PMID:2372509</ref> <ref>PMID:2162822</ref> <ref>PMID:1958666</ref> <ref>PMID:1902289</ref> <ref>PMID:1346975</ref> <ref>PMID:1615485</ref> <ref>PMID:8257988</ref> <ref>PMID:8076946</ref> <ref>PMID:8199596</ref> <ref>PMID:7981722</ref> <ref>PMID:8680410</ref> <ref>PMID:9222764</ref> <ref>PMID:9590153</ref> <ref>PMID:9452115</ref> <ref>PMID:9600455</ref> <ref>PMID:10698280</ref> <ref>PMID:10094553</ref> <ref>PMID:11122099</ref> <ref>PMID:12588353</ref> <ref>PMID:12604421</ref> Note=Mutations in position 43 (Oxford-3, San Dimas) and 46 (Cambridge) prevents cleavage of the propeptide, mutation in position 93 (Alabama) probably fails to bind to cell membranes, mutation in position 191 (Chapel-Hill) or in position 226 (Nagoya OR Hilo) prevent cleavage of the activation peptide. Defects in F9 are the cause of thrombophilia due to factor IX defect (THPH8) [MIM:[https://omim.org/entry/300807 300807]. A hemostatic disorder characterized by a tendency to thrombosis.<ref>PMID:19846852</ref>
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== Function ==
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[https://www.uniprot.org/uniprot/FA9_HUMAN FA9_HUMAN] Factor IX is a vitamin K-dependent plasma protein that participates in the intrinsic pathway of blood coagulation by converting factor X to its active form in the presence of Ca(2+) ions, phospholipids, and factor VIIIa.
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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Two high-throughput screening hits were investigated for SAR against human factor IXa. Both hits feature a benzamide linked to a [6-5]-heteroaryl via an alkyl amine. In the case where this system is a benzimidazolyl-ethyl amine the binding potency for the hit was improved &gt;500-fold, from 9muM to 0.016muM. For the other hit, which contains a tetrahydropyrido-indazole amine, potency was improved 20-fold, from 2muM to 0.09muM. X-ray crystal structures were obtained for an example of each class which improved understanding of the binding, and will enable further drug discovery efforts.
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Authors: Hruza, A., Reichert, P.
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Rapid development of two factor IXa inhibitors from hit to lead.,Parker DL Jr, Walsh S, Li B, Kim E, Sharipour A, Smith C, Chen YH, Berger R, Harper B, Zhang T, Park M, Shu M, Wu J, Xu J, Dewnani S, Sherer EC, Hruza A, Reichert P, Geissler W, Sonatore L, Ellsworth K, Balkovec J, Greenlee W, Wood HB Bioorg Med Chem Lett. 2015 Jun 1;25(11):2321-5. doi: 10.1016/j.bmcl.2015.04.025. , Epub 2015 Apr 13. PMID:25937013<ref>PMID:25937013</ref>
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Description: Rapid development of two Factor IXa inhibitors from Hit to Lead
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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[[Category: Unreleased Structures]]
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</div>
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[[Category: Hruza, A]]
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<div class="pdbe-citations 4z0k" style="background-color:#fffaf0;"></div>
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[[Category: Reichert, P]]
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==See Also==
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*[[Factor IX 3D structures|Factor IX 3D structures]]
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== References ==
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<references/>
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__TOC__
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</StructureSection>
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[[Category: Homo sapiens]]
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[[Category: Large Structures]]
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[[Category: Hruza A]]
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[[Category: Reichert P]]

Current revision

Rapid development of two Factor IXa inhibitors from Hit to Lead

PDB ID 4z0k

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