7v13 - Revision history

OCA at 17:22, 18 October 2023

OCA — Wed, 18 Oct 2023 17:22:09 GMT

←Older revision		Revision as of 17:22, 18 October 2023
Line 4:		Line 4:
	== Structural highlights ==		== Structural highlights ==
	<table><tr><td colspan='2'>[[7v13]] 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=7V13 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7V13 FirstGlance]. <br>		<table><tr><td colspan='2'>[[7v13]] 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=7V13 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7V13 FirstGlance]. <br>
-	</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=ORF:3-chloranyl-4-[1-[(1~{R})-1-[5-[3-chloranyl-2-fluoranyl-6-(1,2,3,4-tetrazol-1-yl)phenyl]-1-oxidanyl-pyridin-2-yl]-2-cyclopropyl-ethyl]pyrazol-4-yl]-5-fluoranyl-pyridine'>ORF</scene></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]] 1.589Å</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=ORF:3-chloranyl-4-[1-[(1~{R})-1-[5-[3-chloranyl-2-fluoranyl-6-(1,2,3,4-tetrazol-1-yl)phenyl]-1-oxidanyl-pyridin-2-yl]-2-cyclopropyl-ethyl]pyrazol-4-yl]-5-fluoranyl-pyridine'>ORF</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=7v13 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7v13 OCA], [https://pdbe.org/7v13 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7v13 RCSB], [https://www.ebi.ac.uk/pdbsum/7v13 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7v13 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=7v13 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7v13 OCA], [https://pdbe.org/7v13 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7v13 RCSB], [https://www.ebi.ac.uk/pdbsum/7v13 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7v13 ProSAT]</span></td></tr>
	</table>		</table>
	== Disease ==		== Disease ==
-	[[https://www.uniprot.org/uniprot/FA11_HUMAN FA11_HUMAN]] Defects in F11 are the cause of factor XI deficiency (FA11D) [MIM:[https://omim.org/entry/612416 612416]]; also known as plasma thromboplastin antecedent deficiency or Rosenthal syndrome. It is a hemorrhagic disease characterized by reduced levels and activity of factor XI resulting in moderate bleeding symptoms, usually occurring after trauma or surgery. Patients usually do not present spontaneous bleeding but women can present with menorrhagia. Hemorrhages are usually moderate.<ref>PMID:2813350</ref> <ref>PMID:1547342</ref> <ref>PMID:7888672</ref> <ref>PMID:7669672</ref> <ref>PMID:9401068</ref> <ref>PMID:9787168</ref> <ref>PMID:10027710</ref> <ref>PMID:10606881</ref> <ref>PMID:11895778</ref> <ref>PMID:15026311</ref> <ref>PMID:15180874</ref> <ref>PMID:15953011</ref> <ref>PMID:16607084</ref> <ref>PMID:18005151</ref> <ref>PMID:21668437</ref> <ref>PMID:21457405</ref> <ref>PMID:22016685</ref> <ref>PMID:22322133</ref> <ref>PMID:21999818</ref> <ref>PMID:22159456</ref>	+	[https://www.uniprot.org/uniprot/FA11_HUMAN FA11_HUMAN] Defects in F11 are the cause of factor XI deficiency (FA11D) [MIM:[https://omim.org/entry/612416 612416]; also known as plasma thromboplastin antecedent deficiency or Rosenthal syndrome. It is a hemorrhagic disease characterized by reduced levels and activity of factor XI resulting in moderate bleeding symptoms, usually occurring after trauma or surgery. Patients usually do not present spontaneous bleeding but women can present with menorrhagia. Hemorrhages are usually moderate.<ref>PMID:2813350</ref> <ref>PMID:1547342</ref> <ref>PMID:7888672</ref> <ref>PMID:7669672</ref> <ref>PMID:9401068</ref> <ref>PMID:9787168</ref> <ref>PMID:10027710</ref> <ref>PMID:10606881</ref> <ref>PMID:11895778</ref> <ref>PMID:15026311</ref> <ref>PMID:15180874</ref> <ref>PMID:15953011</ref> <ref>PMID:16607084</ref> <ref>PMID:18005151</ref> <ref>PMID:21668437</ref> <ref>PMID:21457405</ref> <ref>PMID:22016685</ref> <ref>PMID:22322133</ref> <ref>PMID:21999818</ref> <ref>PMID:22159456</ref>
	== Function ==		== Function ==
-	[[https://www.uniprot.org/uniprot/FA11_HUMAN FA11_HUMAN]] Factor XI triggers the middle phase of the intrinsic pathway of blood coagulation by activating factor IX.	+	[https://www.uniprot.org/uniprot/FA11_HUMAN FA11_HUMAN] Factor XI triggers the middle phase of the intrinsic pathway of blood coagulation by activating factor IX.
	<div style="background-color:#fffaf0;">		<div style="background-color:#fffaf0;">
	== Publication Abstract from PubMed ==		== Publication Abstract from PubMed ==
Line 20:		Line 21:
	</div>		</div>
	<div class="pdbe-citations 7v13" style="background-color:#fffaf0;"></div>		<div class="pdbe-citations 7v13" style="background-color:#fffaf0;"></div>
		+
		+	==See Also==
		+	*[[Factor XIa 3D structures\|Factor XIa 3D structures]]
	== References ==		== References ==
	<references/>		<references/>

OCA at 03:20, 8 September 2022

OCA — Thu, 08 Sep 2022 03:20:22 GMT

←Older revision		Revision as of 03:20, 8 September 2022
Line 1:		Line 1:

	==Factor XIa in Complex with Compound 2g==		==Factor XIa in Complex with Compound 2g==
-	<StructureSection load='7v13' size='340' side='right'caption='[[7v13]]' scene=''>	+	<StructureSection load='7v13' size='340' side='right'caption='[[7v13]], [[Resolution\|resolution]] 1.59Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7V13 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7V13 FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[7v13]] 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=7V13 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7V13 FirstGlance]. <br>
-	</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=7v13 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7v13 OCA], [https://pdbe.org/7v13 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7v13 RCSB], [https://www.ebi.ac.uk/pdbsum/7v13 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7v13 ProSAT]</span></td></tr>	+	</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=ORF:3-chloranyl-4-[1-[(1~{R})-1-[5-[3-chloranyl-2-fluoranyl-6-(1,2,3,4-tetrazol-1-yl)phenyl]-1-oxidanyl-pyridin-2-yl]-2-cyclopropyl-ethyl]pyrazol-4-yl]-5-fluoranyl-pyridine'>ORF</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=7v13 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7v13 OCA], [https://pdbe.org/7v13 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7v13 RCSB], [https://www.ebi.ac.uk/pdbsum/7v13 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7v13 ProSAT]</span></td></tr>
	</table>		</table>
		+	== Disease ==
		+	[[https://www.uniprot.org/uniprot/FA11_HUMAN FA11_HUMAN]] Defects in F11 are the cause of factor XI deficiency (FA11D) [MIM:[https://omim.org/entry/612416 612416]]; also known as plasma thromboplastin antecedent deficiency or Rosenthal syndrome. It is a hemorrhagic disease characterized by reduced levels and activity of factor XI resulting in moderate bleeding symptoms, usually occurring after trauma or surgery. Patients usually do not present spontaneous bleeding but women can present with menorrhagia. Hemorrhages are usually moderate.<ref>PMID:2813350</ref> <ref>PMID:1547342</ref> <ref>PMID:7888672</ref> <ref>PMID:7669672</ref> <ref>PMID:9401068</ref> <ref>PMID:9787168</ref> <ref>PMID:10027710</ref> <ref>PMID:10606881</ref> <ref>PMID:11895778</ref> <ref>PMID:15026311</ref> <ref>PMID:15180874</ref> <ref>PMID:15953011</ref> <ref>PMID:16607084</ref> <ref>PMID:18005151</ref> <ref>PMID:21668437</ref> <ref>PMID:21457405</ref> <ref>PMID:22016685</ref> <ref>PMID:22322133</ref> <ref>PMID:21999818</ref> <ref>PMID:22159456</ref>
		+	== Function ==
		+	[[https://www.uniprot.org/uniprot/FA11_HUMAN FA11_HUMAN]] Factor XI triggers the middle phase of the intrinsic pathway of blood coagulation by activating factor IX.
		+	<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 (Ki = 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 Jul 21. doi: 10.1021/acs.jmedchem.2c00442. PMID:35862732<ref>PMID:35862732</ref>
		+
		+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
		+	</div>
		+	<div class="pdbe-citations 7v13" style="background-color:#fffaf0;"></div>
		+	== References ==
		+	<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
		+	[[Category: Homo sapiens]]
	[[Category: Large Structures]]		[[Category: Large Structures]]
	[[Category: Cedervall P]]		[[Category: Cedervall P]]
	[[Category: Milligan CM]]		[[Category: Milligan CM]]
	[[Category: Shaffer PL]]		[[Category: Shaffer PL]]

OCA at 11:11, 31 August 2022

OCA — Wed, 31 Aug 2022 11:11:50 GMT

←Older revision		Revision as of 11:11, 31 August 2022
Line 1:		Line 1:

	==Factor XIa in Complex with Compound 2g==		==Factor XIa in Complex with Compound 2g==
-	<StructureSection load='7v13' size='340' side='right'caption='[[7v13]]~~, [[Resolution\|resolution]] 1.59Å~~' scene=''>	+	<StructureSection load='7v13' size='340' side='right'caption='[[7v13]]' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>~~[[7v13]] is a 1 chain structure.~~ Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7V13 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7V13 FirstGlance]. <br>	+	<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7V13 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7V13 FirstGlance]. <br>
-	</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=ORF:3-chloranyl-4-[1-[(1~{R})-1-[5-[3-chloranyl-2-fluoranyl-6-(1,2,3,4-tetrazol-1-yl)phenyl]-1-oxidanyl-pyridin-2-yl]-2-cyclopropyl-ethyl]pyrazol-4-yl]-5-fluoranyl-pyridine'>ORF</scene></td></tr>	+	</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=7v13 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7v13 OCA], [https://pdbe.org/7v13 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7v13 RCSB], [https://www.ebi.ac.uk/pdbsum/7v13 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7v13 ProSAT]</span></td></tr>
-	<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Coagulation_factor_XIa Coagulation factor XIa], with EC number [https://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.21.27 3.4.21.27] </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=7v13 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7v13 OCA], [https://pdbe.org/7v13 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7v13 RCSB], [https://www.ebi.ac.uk/pdbsum/7v13 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7v13 ProSAT]</span></td></tr>	+
	</table>		</table>
-	== Disease ==
-	[[https://www.uniprot.org/uniprot/FA11_HUMAN FA11_HUMAN]] Defects in F11 are the cause of factor XI deficiency (FA11D) [MIM:[https://omim.org/entry/612416 612416]]; also known as plasma thromboplastin antecedent deficiency or Rosenthal syndrome. It is a hemorrhagic disease characterized by reduced levels and activity of factor XI resulting in moderate bleeding symptoms, usually occurring after trauma or surgery. Patients usually do not present spontaneous bleeding but women can present with menorrhagia. Hemorrhages are usually moderate.<ref>PMID:2813350</ref> <ref>PMID:1547342</ref> <ref>PMID:7888672</ref> <ref>PMID:7669672</ref> <ref>PMID:9401068</ref> <ref>PMID:9787168</ref> <ref>PMID:10027710</ref> <ref>PMID:10606881</ref> <ref>PMID:11895778</ref> <ref>PMID:15026311</ref> <ref>PMID:15180874</ref> <ref>PMID:15953011</ref> <ref>PMID:16607084</ref> <ref>PMID:18005151</ref> <ref>PMID:21668437</ref> <ref>PMID:21457405</ref> <ref>PMID:22016685</ref> <ref>PMID:22322133</ref> <ref>PMID:21999818</ref> <ref>PMID:22159456</ref>
-	== Function ==
-	[[https://www.uniprot.org/uniprot/FA11_HUMAN FA11_HUMAN]] Factor XI triggers the middle phase of the intrinsic pathway of blood coagulation by activating factor IX.
-	<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 (Ki = 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 Jul 21. doi: 10.1021/acs.jmedchem.2c00442. PMID:35862732<ref>PMID:35862732</ref>
-
-	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-	</div>
-	<div class="pdbe-citations 7v13" style="background-color:#fffaf0;"></div>
-	== References ==
-	<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
-	[[Category: Coagulation factor XIa]]
	[[Category: Large Structures]]		[[Category: Large Structures]]
-	[[Category: Cedervall, P]]	+	[[Category: Cedervall P]]
-	[[Category: Milligan~~, C M~~]]	+	[[Category: Milligan CM]]
-	[[Category: Shaffer~~, P L]]~~	+	[[Category: Shaffer PL]]
-	~~[[Category: Blood clotting]]~~	+
-	~~[[Category: Coagulation factor]]~~	+
-	~~[[Category: Hydrolase]]~~	+
-	~~[[Category: Serine protease~~]]	+

OCA at 05:15, 25 August 2022

OCA — Thu, 25 Aug 2022 05:15:33 GMT

←Older revision		Revision as of 05:15, 25 August 2022
Line 1:		Line 1:

	==Factor XIa in Complex with Compound 2g==		==Factor XIa in Complex with Compound 2g==
-	<StructureSection load='7v13' size='340' side='right'caption='[[7v13]]' scene=''>	+	<StructureSection load='7v13' size='340' side='right'caption='[[7v13]], [[Resolution\|resolution]] 1.59Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7V13 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7V13 FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[7v13]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7V13 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7V13 FirstGlance]. <br>
-	</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=7v13 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7v13 OCA], [https://pdbe.org/7v13 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7v13 RCSB], [https://www.ebi.ac.uk/pdbsum/7v13 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7v13 ProSAT]</span></td></tr>	+	</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=ORF:3-chloranyl-4-[1-[(1~{R})-1-[5-[3-chloranyl-2-fluoranyl-6-(1,2,3,4-tetrazol-1-yl)phenyl]-1-oxidanyl-pyridin-2-yl]-2-cyclopropyl-ethyl]pyrazol-4-yl]-5-fluoranyl-pyridine'>ORF</scene></td></tr>
		+	<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Coagulation_factor_XIa Coagulation factor XIa], with EC number [https://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.21.27 3.4.21.27] </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=7v13 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7v13 OCA], [https://pdbe.org/7v13 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7v13 RCSB], [https://www.ebi.ac.uk/pdbsum/7v13 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7v13 ProSAT]</span></td></tr>
	</table>		</table>
		+	== Disease ==
		+	[[https://www.uniprot.org/uniprot/FA11_HUMAN FA11_HUMAN]] Defects in F11 are the cause of factor XI deficiency (FA11D) [MIM:[https://omim.org/entry/612416 612416]]; also known as plasma thromboplastin antecedent deficiency or Rosenthal syndrome. It is a hemorrhagic disease characterized by reduced levels and activity of factor XI resulting in moderate bleeding symptoms, usually occurring after trauma or surgery. Patients usually do not present spontaneous bleeding but women can present with menorrhagia. Hemorrhages are usually moderate.<ref>PMID:2813350</ref> <ref>PMID:1547342</ref> <ref>PMID:7888672</ref> <ref>PMID:7669672</ref> <ref>PMID:9401068</ref> <ref>PMID:9787168</ref> <ref>PMID:10027710</ref> <ref>PMID:10606881</ref> <ref>PMID:11895778</ref> <ref>PMID:15026311</ref> <ref>PMID:15180874</ref> <ref>PMID:15953011</ref> <ref>PMID:16607084</ref> <ref>PMID:18005151</ref> <ref>PMID:21668437</ref> <ref>PMID:21457405</ref> <ref>PMID:22016685</ref> <ref>PMID:22322133</ref> <ref>PMID:21999818</ref> <ref>PMID:22159456</ref>
		+	== Function ==
		+	[[https://www.uniprot.org/uniprot/FA11_HUMAN FA11_HUMAN]] Factor XI triggers the middle phase of the intrinsic pathway of blood coagulation by activating factor IX.
		+	<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 (Ki = 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 Jul 21. doi: 10.1021/acs.jmedchem.2c00442. PMID:35862732<ref>PMID:35862732</ref>
		+
		+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
		+	</div>
		+	<div class="pdbe-citations 7v13" style="background-color:#fffaf0;"></div>
		+	== References ==
		+	<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
		+	[[Category: Coagulation factor XIa]]
	[[Category: Large Structures]]		[[Category: Large Structures]]
-	[[Category: Cedervall P]]	+	[[Category: Cedervall, P]]
-	[[Category: Milligan CM]]	+	[[Category: Milligan, C M]]
-	[[Category: Shaffer PL]]	+	[[Category: Shaffer, P L]]
		+	[[Category: Blood clotting]]
		+	[[Category: Coagulation factor]]
		+	[[Category: Hydrolase]]
		+	[[Category: Serine protease]]

OCA at 04:54, 3 August 2022

OCA — Wed, 03 Aug 2022 04:54:11 GMT

←Older revision		Revision as of 04:54, 3 August 2022
Line 1:		Line 1:
-	'''Unreleased structure'''

-	~~The entry~~ 7v13 ~~is ON HOLD until Paper Publication~~	+	==Factor XIa in Complex with Compound 2g==
-		+	<StructureSection load='7v13' size='340' side='right'caption='[[7v13]]' scene=''>
-	~~Authors~~: ~~Shaffer~~, P.L., ~~Milligan~~, C.M., ~~Cedervall~~, P.	+	== Structural highlights ==
-		+	<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7V13 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7V13 FirstGlance]. <br>
-	~~Description: Factor XIa in Complex with Compound 2g~~	+	</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=7v13 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7v13 OCA], [https://pdbe.org/7v13 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7v13 RCSB], [https://www.ebi.ac.uk/pdbsum/7v13 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7v13 ProSAT]</span></td></tr>
-	[[Category: ~~Unreleased~~ Structures]]	+	</table>
-	[[Category: Cedervall, P]]	+	__TOC__
-	[[Category: Milligan~~, C.M~~]]	+	</StructureSection>
-	[[Category: Shaffer~~, P.L~~]]	+	[[Category: Large Structures]]
		+	[[Category: Cedervall P]]
		+	[[Category: Milligan CM]]
		+	[[Category: Shaffer PL]]

OCA at 03:52, 15 June 2022

OCA — Wed, 15 Jun 2022 03:52:45 GMT

←Older revision		Revision as of 03:52, 15 June 2022
Line 1:		Line 1:
	'''Unreleased structure'''		'''Unreleased structure'''

-	The entry 7v13 is ON HOLD	+	The entry 7v13 is ON HOLD until Paper Publication

	Authors: Shaffer, P.L., Milligan, C.M., Cedervall, P.		Authors: Shaffer, P.L., Milligan, C.M., Cedervall, P.

OCA: Protected "7v13" [edit=sysop:move=sysop]

OCA — Wed, 18 May 2022 09:07:27 GMT

Protected "7v13" [edit=sysop:move=sysop]

←Older revision

Revision as of 09:07, 18 May 2022

OCA: New page: '''Unreleased structure''' The entry 7v13 is ON HOLD Authors: Shaffer, P.L., Milligan, C.M., Cedervall, P. Description: Factor XIa in Complex with Compound 2g [[Category: Unreleased St...

OCA — Wed, 18 May 2022 09:07:26 GMT

New page: '''Unreleased structure''' The entry 7v13 is ON HOLD Authors: Shaffer, P.L., Milligan, C.M., Cedervall, P. Description: Factor XIa in Complex with Compound 2g [[Category: Unreleased St...

New page

'''Unreleased structure'''

The entry 7v13 is ON HOLD

Authors: Shaffer, P.L., Milligan, C.M., Cedervall, P.

Description: Factor XIa in Complex with Compound 2g
[[Category: Unreleased Structures]]
[[Category: Cedervall, P]]
[[Category: Milligan, C.M]]
[[Category: Shaffer, P.L]]