6ts7: Difference between revisions
New page: '''Unreleased structure''' The entry 6ts7 is ON HOLD Authors: Renatus, M., Schiering, N. Description: human plasmakallikrein protease domain in complex with active site directed inhibi... |
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The | ==Coagulation factor XI protease domain in complex with active site inhibitor== | ||
<StructureSection load='6ts7' size='340' side='right'caption='[[6ts7]], [[Resolution|resolution]] 2.63Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6TS7 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6TS7 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]] 2.63Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=NWE:2-[2-[[3-(1,2,3,4-tetrahydroisoquinolin-7-yl)phenyl]methoxy]phenyl]ethanoic+acid'>NWE</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=6ts7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6ts7 OCA], [https://pdbe.org/6ts7 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6ts7 RCSB], [https://www.ebi.ac.uk/pdbsum/6ts7 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6ts7 ProSAT]</span></td></tr> | |||
</table> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
The serine protease Factor XI (FXI) is a prominent drug target as it holds promise to deliver efficacious anti-coagulation without an enhanced risk of major bleeds. Several efforts have been described targeting the active form of the enzyme, FXIa. Herein we disclose our efforts to identify potent, selective, and orally bioavailable inhibitors of FXIa. Compound 1, identified from a diverse library of internal serine protease inhibitors, was originally designed as a complement Factor D inhibitor and exhibited sub-micromolar FXIa activity and an encouraging ADME profile while being devoid of peptidomimetic architecture. Optimization of interactions in the S1, S1beta, and S1` pockets of FXIa through a combination of structure-based drug design and traditional medicinal chemistry led to the discovery of compound 23 with sub-nanomolar potency on FXIa, enhanced selectivity over other coagulation proteases, and a pre-clinical PK profile consistent with bid dosing in patients. | |||
Structure-based design and pre-clinical characterization of selective and orally bioavailable Factor XIa inhibitors: Demonstrating the power of an integrated S1 protease family approach.,Lorthiois E, Roache J, Barnes-Seeman D, Altmann E, Hassiepen U, Turner G, Duvadie R, Hornak V, Karki RG, Schiering N, Weihofen WA, Perruccio F, Calhoun A, Fazal T, Dedic D, Durand C, Dussauge S, Fettis K, Tritsch F, Dentel C, Druet A, Liu D, Kirman L, Lachal J, Namoto K, Bevan D, Mo R, Monnet G, Muller L, Zessis R, Huang X, Lindsley L, Currie T, Chiu YH, Fridrich C, Delgado P, Wang S, Hollis-Symynkywicz M, Berghausen J, Williams E, Liu H, Liang G, Kim H, Hoffmann P, Hein A, Ramage P, D'Arcy A, Harlfinger S, Renatus M, Ruedisser S, Feldman D, Elliott J, Sedrani RC, Maibaum J, Adams CM J Med Chem. 2020 Jun 17. doi: 10.1021/acs.jmedchem.0c00279. PMID:32551603<ref>PMID:32551603</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
[[Category: | <div class="pdbe-citations 6ts7" style="background-color:#fffaf0;"></div> | ||
[[Category: | |||
==See Also== | |||
*[[Factor XIa 3D structures|Factor XIa 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Large Structures]] | |||
[[Category: Renatus M]] | |||
[[Category: Schiering N]] | |||