7v0z - Revision history

OCA at 17:22, 18 October 2023

2023-10-18T17:22:03Z

←Older revision		Revision as of 17:22, 18 October 2023
Line 4:		Line 4:
	== Structural highlights ==		== Structural highlights ==
	<table><tr><td colspan='2'>[[7v0z]] 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=7V0Z OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7V0Z FirstGlance]. <br>		<table><tr><td colspan='2'>[[7v0z]] 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=7V0Z OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7V0Z FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=OQ6:methyl+~{N}-[4-[1-[(1~{R})-1-[5-[5-chloranyl-2-(1,2,3,4-tetrazol-1-yl)phenyl]-1-oxidanyl-pyridin-2-yl]-2-cyclopropyl-ethyl]pyrazol-4-yl]phenyl]carbamate'>OQ6</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]] 1.8Å</td></tr>
		+	<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=OQ6:methyl+~{N}-[4-[1-[(1~{R})-1-[5-[5-chloranyl-2-(1,2,3,4-tetrazol-1-yl)phenyl]-1-oxidanyl-pyridin-2-yl]-2-cyclopropyl-ethyl]pyrazol-4-yl]phenyl]carbamate'>OQ6</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=7v0z FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7v0z OCA], [https://pdbe.org/7v0z PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7v0z RCSB], [https://www.ebi.ac.uk/pdbsum/7v0z PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7v0z 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=7v0z FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7v0z OCA], [https://pdbe.org/7v0z PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7v0z RCSB], [https://www.ebi.ac.uk/pdbsum/7v0z PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7v0z 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 7v0z" style="background-color:#fffaf0;"></div>		<div class="pdbe-citations 7v0z" 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

2022-09-08T03:20:09Z

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

	==Factor XIa in Complex with Compound 2a==		==Factor XIa in Complex with Compound 2a==
-	<StructureSection load='7v0z' size='340' side='right'caption='[[7v0z]]' scene=''>	+	<StructureSection load='7v0z' size='340' side='right'caption='[[7v0z]], [[Resolution\|resolution]] 1.80Å' 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=7V0Z OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7V0Z FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[7v0z]] 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=7V0Z OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7V0Z 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=7v0z FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7v0z OCA], [https://pdbe.org/7v0z PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7v0z RCSB], [https://www.ebi.ac.uk/pdbsum/7v0z PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7v0z 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=OQ6:methyl+~{N}-[4-[1-[(1~{R})-1-[5-[5-chloranyl-2-(1,2,3,4-tetrazol-1-yl)phenyl]-1-oxidanyl-pyridin-2-yl]-2-cyclopropyl-ethyl]pyrazol-4-yl]phenyl]carbamate'>OQ6</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=7v0z FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7v0z OCA], [https://pdbe.org/7v0z PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7v0z RCSB], [https://www.ebi.ac.uk/pdbsum/7v0z PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7v0z 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 7v0z" style="background-color:#fffaf0;"></div>
		+	== References ==
		+	<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
		+	[[Category: Homo sapiens]]
	[[Category: Large Structures]]		[[Category: Large Structures]]
	[[Category: Milligan CM]]		[[Category: Milligan CM]]
	[[Category: Shaffer PL]]		[[Category: Shaffer PL]]
	[[Category: Spurlino J]]		[[Category: Spurlino J]]

OCA at 11:11, 31 August 2022

2022-08-31T11:11:39Z

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

	==Factor XIa in Complex with Compound 2a==		==Factor XIa in Complex with Compound 2a==
-	<StructureSection load='7v0z' size='340' side='right'caption='[[7v0z]]~~, [[Resolution\|resolution]] 1.80Å~~' scene=''>	+	<StructureSection load='7v0z' size='340' side='right'caption='[[7v0z]]' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>~~[[7v0z]] is a 1 chain structure.~~ Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7V0Z OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7V0Z FirstGlance]. <br>	+	<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7V0Z OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7V0Z FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=OQ6:methyl+~{N}-[4-[1-[(1~{R})-1-[5-[5-chloranyl-2-(1,2,3,4-tetrazol-1-yl)phenyl]-1-oxidanyl-pyridin-2-yl]-2-cyclopropyl-ethyl]pyrazol-4-yl]phenyl]carbamate'>OQ6</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=7v0z FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7v0z OCA], [https://pdbe.org/7v0z PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7v0z RCSB], [https://www.ebi.ac.uk/pdbsum/7v0z PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7v0z 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=7v0z FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7v0z OCA], [https://pdbe.org/7v0z PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7v0z RCSB], [https://www.ebi.ac.uk/pdbsum/7v0z PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7v0z 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 7v0z" style="background-color:#fffaf0;"></div>
-	== References ==
-	<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
-	[[Category: Coagulation factor XIa]]
	[[Category: Large Structures]]		[[Category: Large Structures]]
-	[[Category: Milligan~~, C M~~]]	+	[[Category: Milligan CM]]
-	[[Category: Shaffer~~, P L~~]]	+	[[Category: Shaffer PL]]
-	[[Category: Spurlino, J]]	+	[[Category: Spurlino J]]
-	~~[[Category: Blood clotting]]~~	+
-	~~[[Category: Coagulation factor]]~~	+
-	~~[[Category: Hydrolase]]~~	+
-	~~[[Category: Serine protease~~]]	+

OCA at 05:15, 25 August 2022

2022-08-25T05:15:22Z

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

	==Factor XIa in Complex with Compound 2a==		==Factor XIa in Complex with Compound 2a==
-	<StructureSection load='7v0z' size='340' side='right'caption='[[7v0z]]' scene=''>	+	<StructureSection load='7v0z' size='340' side='right'caption='[[7v0z]], [[Resolution\|resolution]] 1.80Å' 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=7V0Z OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7V0Z FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[7v0z]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7V0Z OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7V0Z 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=7v0z FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7v0z OCA], [https://pdbe.org/7v0z PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7v0z RCSB], [https://www.ebi.ac.uk/pdbsum/7v0z PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7v0z 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=OQ6:methyl+~{N}-[4-[1-[(1~{R})-1-[5-[5-chloranyl-2-(1,2,3,4-tetrazol-1-yl)phenyl]-1-oxidanyl-pyridin-2-yl]-2-cyclopropyl-ethyl]pyrazol-4-yl]phenyl]carbamate'>OQ6</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=7v0z FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7v0z OCA], [https://pdbe.org/7v0z PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7v0z RCSB], [https://www.ebi.ac.uk/pdbsum/7v0z PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7v0z 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 7v0z" style="background-color:#fffaf0;"></div>
		+	== References ==
		+	<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
		+	[[Category: Coagulation factor XIa]]
	[[Category: Large Structures]]		[[Category: Large Structures]]
-	[[Category: Milligan CM]]	+	[[Category: Milligan, C M]]
-	[[Category: Shaffer PL]]	+	[[Category: Shaffer, P L]]
-	[[Category: Spurlino J]]	+	[[Category: Spurlino, J]]
		+	[[Category: Blood clotting]]
		+	[[Category: Coagulation factor]]
		+	[[Category: Hydrolase]]
		+	[[Category: Serine protease]]

OCA at 04:54, 3 August 2022

2022-08-03T04:54:04Z

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

-	~~The entry~~ 7v0z ~~is ON HOLD until Paper Publication~~	+	==Factor XIa in Complex with Compound 2a==
-		+	<StructureSection load='7v0z' size='340' side='right'caption='[[7v0z]]' scene=''>
-	~~Authors~~: ~~Shaffer~~, P.L., ~~Spurlino~~, J., ~~Milligan~~, C.M.	+	== Structural highlights ==
-		+	<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7V0Z OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7V0Z FirstGlance]. <br>
-	~~Description: Factor XIa in Complex with Compound 2a~~	+	</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=7v0z FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7v0z OCA], [https://pdbe.org/7v0z PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7v0z RCSB], [https://www.ebi.ac.uk/pdbsum/7v0z PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7v0z ProSAT]</span></td></tr>
-	[[Category: ~~Unreleased~~ Structures]]	+	</table>
-	[[Category: Milligan~~, C.M~~]]	+	__TOC__
-	[[Category: ~~Spurlino, J~~]]	+	</StructureSection>
-	[[Category: ~~Shaffer, P.L~~]]	+	[[Category: Large Structures]]
		+	[[Category: Milligan CM]]
		+	[[Category: Shaffer PL]]
		+	[[Category: Spurlino J]]

OCA at 03:52, 15 June 2022

2022-06-15T03:52:36Z

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

-	The entry 7v0z is ON HOLD	+	The entry 7v0z is ON HOLD until Paper Publication

	Authors: Shaffer, P.L., Spurlino, J., Milligan, C.M.		Authors: Shaffer, P.L., Spurlino, J., Milligan, C.M.

OCA: Protected "7v0z" [edit=sysop:move=sysop]

2022-05-18T09:07:14Z

Protected "7v0z" [edit=sysop:move=sysop]

←Older revision

Revision as of 09:07, 18 May 2022

OCA: New page: '''Unreleased structure''' The entry 7v0z is ON HOLD Authors: Shaffer, P.L., Spurlino, J., Milligan, C.M. Description: Factor XIa in Complex with Compound 2a [[Category: Unreleased Str...

2022-05-18T09:07:13Z

New page: '''Unreleased structure''' The entry 7v0z is ON HOLD Authors: Shaffer, P.L., Spurlino, J., Milligan, C.M. Description: Factor XIa in Complex with Compound 2a [[Category: Unreleased Str...

New page

'''Unreleased structure'''

The entry 7v0z is ON HOLD

Authors: Shaffer, P.L., Spurlino, J., Milligan, C.M.

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