View source for 5tnt


==Discovery of novel aminobenzisoxazole derivatives as orally available factor IXa inhibitors==
<StructureSection load='5tnt' size='340' side='right'caption='[[5tnt]], [[Resolution|resolution]] 1.40&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[5tnt]] 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=5TNT OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5TNT 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]] 1.4&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=7GQ:N-[(1S,4S,7R)-2-(3-AMINO-4-CHLORO[1,2]OXAZOLO[5,4-C]PYRIDIN-7-YL)-2-AZABICYCLO[2.2.1]HEPTAN-7-YL]-2-CHLORO-4-(3-METHYL-1H-1,2,4-TRIAZOL-1-YL)BENZAMIDE'>7GQ</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=NHE:2-[N-CYCLOHEXYLAMINO]ETHANE+SULFONIC+ACID'>NHE</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=5tnt FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5tnt OCA], [https://pdbe.org/5tnt PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5tnt RCSB], [https://www.ebi.ac.uk/pdbsum/5tnt PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5tnt ProSAT]</span></td></tr>
</table>
== Disease ==
[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> 
== Function ==
[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.
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Using structure based drug design, novel aminobenzisoxazoles as coagulation factor IXa inhibitors were designed and synthesized. Highly selective inhibition of FIXa over FXa was demonstrated. Anticoagulation profile of selected compounds was evaluated by aPTT and PT tests. In vitro ADMET and pharmacokinetic (PK) profiles were also evaluated.

Discovery of novel aminobenzisoxazole derivatives as orally available factor IXa inhibitors.,Sakurada I, Endo T, Hikita K, Hirabayashi T, Hosaka Y, Kato Y, Maeda Y, Matsumoto S, Mizuno T, Nagasue H, Nishimura T, Shimada S, Shinozaki M, Taguchi K, Takeuchi K, Yokoyama T, Hruza A, Reichert P, Zhang T, Wood HB, Nakao K, Furusako S Bioorg Med Chem Lett. 2017 Mar 6. pii: S0960-894X(17)30225-1. doi:, 10.1016/j.bmcl.2017.03.002. PMID:28408226<ref>PMID:28408226</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 5tnt" style="background-color:#fffaf0;"></div>

==See Also==
*[[Factor IX 3D structures|Factor IX 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Endo T]]
[[Category: Furusako S]]
[[Category: Hikita K]]
[[Category: Hirabayashi T]]
[[Category: Hosaka Y]]
[[Category: Hruza A]]
[[Category: Kato Y]]
[[Category: Maeda Y]]
[[Category: Matsumoto S]]
[[Category: Mizuno T]]
[[Category: Nagasue A]]
[[Category: Nakao K]]
[[Category: Nishimura T]]
[[Category: Reichert P]]
[[Category: Sakurada I]]
[[Category: Shimada S]]
[[Category: Shinozaki M]]
[[Category: Taguchi K]]
[[Category: Takeuchi K]]
[[Category: Wood HB]]
[[Category: Yokoyama T]]
[[Category: Zhang T]]