View source for 7v17


==Factor XIa in Complex with Compound 2k==
<StructureSection load='7v17' size='340' side='right'caption='[[7v17]], [[Resolution|resolution]] 1.52&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[7v17]] 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=7V17 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7V17 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]] 1.522&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CIT:CITRIC+ACID'>CIT</scene>, <scene name='pdbligand=OTL:5-[3-chloranyl-2-fluoranyl-6-(1,2,3,4-tetrazol-1-yl)phenyl]-2-[(1~{R})-2-cyclopropyl-1-[4-(3-methylimidazol-4-yl)pyrazol-1-yl]ethyl]-1-oxidanidyl-pyridin-1-ium'>OTL</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=7v17 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7v17 OCA], [https://pdbe.org/7v17 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7v17 RCSB], [https://www.ebi.ac.uk/pdbsum/7v17 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7v17 ProSAT]</span></td></tr>
</table>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Activated factor XI (FXIa) inhibitors are promising novel anticoagulants with low bleeding risk compared with current anticoagulants. The discovery of potent FXIa inhibitors with good oral bioavailability has been challenging. Herein, we describe our discovery effort, utilizing nonclassical interactions to improve potency, cellular permeability, and oral bioavailability by enhancing the binding while reducing polar atoms. Beginning with literature-inspired pyridine N-oxide-based FXIa inhibitor 1, the imidazole linker was first replaced with a pyrazole moiety to establish a polar C-H...water hydrogen-bonding interaction. Then, structure-based drug design was employed to modify lead molecule 2d in the P1' and P2' regions, with substituents interacting with key residues through various nonclassical interactions. As a result, a potent FXIa inhibitor 3f (K(i) = 0.17 nM) was discovered. This compound demonstrated oral bioavailability in preclinical species (rat 36.4%, dog 80.5%, and monkey 43.0%) and displayed a dose-dependent antithrombotic effect in a rabbit arteriovenous shunt model of thrombosis.

Discovery of Potent and Orally Bioavailable Pyridine N-Oxide-Based Factor XIa Inhibitors through Exploiting Nonclassical Interactions.,Xu G, Liu Z, Wang X, Lu T, DesJarlais RL, Thieu T, Zhang J, Devine ZH, Du F, Li Q, Milligan CM, Shaffer P, Cedervall PE, Spurlino JC, Stratton CF, Pietrak B, Szewczuk LM, Wong V, Steele RA, Bruinzeel W, Chintala M, Silva J, Gaul MD, Macielag MJ, Nargund R J Med Chem. 2022 Aug 11;65(15):10419-10440. doi: 10.1021/acs.jmedchem.2c00442. , Epub 2022 Jul 21. PMID:35862732<ref>PMID:35862732</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 7v17" style="background-color:#fffaf0;"></div>

==See Also==
*[[Factor XIa 3D structures|Factor XIa 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Cedervall P]]
[[Category: Milligan CM]]
[[Category: Shaffer PL]]