7v10: Difference between revisions
Jump to navigation
Jump to search
No edit summary |
No edit summary |
||
| Line 5: | Line 5: | ||
<table><tr><td colspan='2'>[[7v10]] 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=7V10 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7V10 FirstGlance]. <br> | <table><tr><td colspan='2'>[[7v10]] 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=7V10 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7V10 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]] 1.798Å</td></tr> | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.798Å</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=OQI:methyl+~{N}-[4-[1-[(1~{R})-1-[5-[3-chloranyl-2-fluoranyl-6-(1,2,3,4-tetrazol-1-yl)phenyl]-1- | <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=OQI:methyl+~{N}-[4-[1-[(1~{R})-1-[5-[3-chloranyl-2-fluoranyl-6-(1,2,3,4-tetrazol-1-yl)phenyl]-1-oxidanidyl-pyridin-1-ium-2-yl]-2-cyclopropyl-ethyl]pyrazol-4-yl]phenyl]carbamate'>OQI</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=7v10 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7v10 OCA], [https://pdbe.org/7v10 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7v10 RCSB], [https://www.ebi.ac.uk/pdbsum/7v10 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7v10 ProSAT]</span></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=7v10 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7v10 OCA], [https://pdbe.org/7v10 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7v10 RCSB], [https://www.ebi.ac.uk/pdbsum/7v10 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7v10 ProSAT]</span></td></tr> | ||
</table> | </table> | ||
<div style="background-color:#fffaf0;"> | <div style="background-color:#fffaf0;"> | ||
== Publication Abstract from PubMed == | == 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 ( | 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 | 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®/PubMed®, a database of the U.S. National Library of Medicine.<br> | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
Latest revision as of 12:15, 17 October 2024
Factor XIa in Complex with Compound 2dFactor XIa in Complex with Compound 2d
Structural highlights
Publication Abstract from PubMedActivated 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[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
|
| ||||||||||||||||||