7e0p - Revision history

OCA at 16:44, 29 November 2023

2023-11-29T16:44:17Z

←Older revision		Revision as of 16:44, 29 November 2023
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	==Crystal Structure of Human Indoleamine 2,3-dioxygenagse 1 (hIDO1) Complexed with 4-(((6-Bromo-1H-indazol-4-yl)amino)methyl)phenol (2)==		==Crystal Structure of Human Indoleamine 2,3-dioxygenagse 1 (hIDO1) Complexed with 4-(((6-Bromo-1H-indazol-4-yl)amino)methyl)phenol (2)==
-	<StructureSection load='7e0p' size='340' side='right'caption='[[7e0p]]' scene=''>	+	<StructureSection load='7e0p' size='340' side='right'caption='[[7e0p]], [[Resolution\|resolution]] 2.63Å' 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=7E0P OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7E0P FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[7e0p]] is a 2 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=7E0P OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7E0P 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=7e0p FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7e0p OCA], [https://pdbe.org/7e0p PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7e0p RCSB], [https://www.ebi.ac.uk/pdbsum/7e0p PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7e0p ProSAT]</span></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]] 2.635Å</td></tr>
		+	<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ACY:ACETIC+ACID'>ACY</scene>, <scene name='pdbligand=HEM:PROTOPORPHYRIN+IX+CONTAINING+FE'>HEM</scene>, <scene name='pdbligand=HU0:4-[[(6-bromanyl-1~{H}-indazol-4-yl)amino]methyl]phenol'>HU0</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=7e0p FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7e0p OCA], [https://pdbe.org/7e0p PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7e0p RCSB], [https://www.ebi.ac.uk/pdbsum/7e0p PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7e0p ProSAT]</span></td></tr>
	</table>		</table>
		+	== Function ==
		+	[https://www.uniprot.org/uniprot/I23O1_HUMAN I23O1_HUMAN] Catalyzes the cleavage of the pyrrol ring of tryptophan and incorporates both atoms of a molecule of oxygen.<ref>PMID:17671174</ref>
		+	<div style="background-color:#fffaf0;">
		+	== Publication Abstract from PubMed ==
		+	Human indoleamine 2,3-dioxygenase 1 (hIDO1) and tryptophan 2,3-dioxygenase (hTDO) have been closely linked to the pathogenesis of Parkinson's disease (PD); nevertheless, development of dual hIDO1 and hTDO inhibitors to evaluate their potential efficacy against PD is still lacking. Here, we report biochemical, biophysical, and computational analyses revealing that 1H-indazole-4-amines inhibit both hIDO1 and hTDO by a mechanism involving direct coordination with the heme ferrous and ferric states. Crystal structure-guided optimization led to 23, which manifested IC50 values of 0.64 and 0.04 muM to hIDO1 and hTDO, respectively, and had good pharmacokinetic properties and brain penetration in mice. 23 showed efficacy against the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced mouse motor coordination deficits, comparable to Madopar, an anti-PD medicine. Further studies revealed that different from Madopar, 23 likely has specific anti-PD mechanisms involving lowering IDO1 expression, alleviating dopaminergic neurodegeneration, reducing inflammatory cytokines and quinolinic acid in mouse brain, and increasing kynurenic acid in mouse blood.
		+
		+	X-ray Structure-Guided Discovery of a Potent, Orally Bioavailable, Dual Human Indoleamine/Tryptophan 2,3-Dioxygenase (hIDO/hTDO) Inhibitor That Shows Activity in a Mouse Model of Parkinson's Disease.,Ning XL, Li YZ, Huo C, Deng J, Gao C, Zhu KR, Wang M, Wu YX, Yu JL, Ren YL, Luo ZY, Li G, Chen Y, Wang SY, Peng C, Yang LL, Wang ZY, Wu Y, Qian S, Li GB J Med Chem. 2021 Jun 24;64(12):8303-8332. doi: 10.1021/acs.jmedchem.1c00303. Epub, 2021 Jun 10. PMID:34110158<ref>PMID:34110158</ref>
		+
		+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
		+	</div>
		+	<div class="pdbe-citations 7e0p" style="background-color:#fffaf0;"></div>
		+
		+	==See Also==
		+	*[[Dioxygenase 3D structures\|Dioxygenase 3D structures]]
		+	== References ==
		+	<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
		+	[[Category: Homo sapiens]]
	[[Category: Large Structures]]		[[Category: Large Structures]]
	[[Category: Li G-B]]		[[Category: Li G-B]]
	[[Category: Ning X-L]]		[[Category: Ning X-L]]

OCA at 08:57, 21 July 2021

2021-07-21T08:57:20Z

←Older revision		Revision as of 08:57, 21 July 2021
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-	'''Unreleased structure'''

-	~~The entry 7e0p is ON HOLD until Paper Publication~~	+	==Crystal Structure of Human Indoleamine 2,3-dioxygenagse 1 (hIDO1) Complexed with 4-(((6-Bromo-1H-indazol-4-yl)amino)methyl)phenol (2)==
-		+	<StructureSection load='7e0p' size='340' side='right'caption='[[7e0p]]' scene=''>
-	~~Authors: Li, G.-B., Ning, X.-L.~~	+	== Structural highlights ==
-		+	<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7E0P OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7E0P FirstGlance]. <br>
-	~~Description:~~ Crystal Structure of Human Indoleamine 2,3-dioxygenagse 1 (hIDO1) Complexed with 4-(((6-Bromo-1H-indazol-4-yl)amino)methyl)phenol (2)	+	</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=7e0p FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7e0p OCA], [https://pdbe.org/7e0p PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7e0p RCSB], [https://www.ebi.ac.uk/pdbsum/7e0p PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7e0p ProSAT]</span></td></tr>
-	[[Category: ~~Unreleased~~ Structures]]	+	</table>
-	[[Category: Li, G.-B]]	+	__TOC__
-	[[Category: Ning, X.-L]]	+	</StructureSection>
		+	[[Category: Large Structures]]
		+	[[Category: Li G-B]]
		+	[[Category: Ning X-L]]

OCA at 09:13, 31 March 2021

2021-03-31T09:13:38Z

←Older revision		Revision as of 09:13, 31 March 2021
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	'''Unreleased structure'''		'''Unreleased structure'''

-	The entry 7e0p is ON HOLD	+	The entry 7e0p is ON HOLD until Paper Publication

	Authors: Li, G.-B., Ning, X.-L.		Authors: Li, G.-B., Ning, X.-L.
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	Description: Crystal Structure of Human Indoleamine 2,3-dioxygenagse 1 (hIDO1) Complexed with 4-(((6-Bromo-1H-indazol-4-yl)amino)methyl)phenol (2)		Description: Crystal Structure of Human Indoleamine 2,3-dioxygenagse 1 (hIDO1) Complexed with 4-(((6-Bromo-1H-indazol-4-yl)amino)methyl)phenol (2)
	[[Category: Unreleased Structures]]		[[Category: Unreleased Structures]]
-	[[Category: Ning, X.-L]]
	[[Category: Li, G.-B]]		[[Category: Li, G.-B]]
		+	[[Category: Ning, X.-L]]

OCA at 05:15, 17 March 2021

2021-03-17T05:15:15Z

←Older revision		Revision as of 05:15, 17 March 2021
Line 5:		Line 5:
	Authors: Li, G.-B., Ning, X.-L.		Authors: Li, G.-B., Ning, X.-L.

-	Description: ~~X-ray~~ Structure~~-Guided Discovery~~ of ~~a Potent, Orally Bioavailable, Dual~~ Human Indoleamine~~/Tryptophan~~ 2,3-~~Dioxygenase~~ (~~hIDO/hTDO~~) ~~Inhibitor that Showed Activity in a Mouse Model of Parkinson's Diseases~~	+	Description: Crystal Structure of Human Indoleamine 2,3-dioxygenagse 1 (hIDO1) Complexed with 4-(((6-Bromo-1H-indazol-4-yl)amino)methyl)phenol (2)
	[[Category: Unreleased Structures]]		[[Category: Unreleased Structures]]
-	[[Category: Li, G.-B]]
	[[Category: Ning, X.-L]]		[[Category: Ning, X.-L]]
		+	[[Category: Li, G.-B]]

OCA: Protected "7e0p" [edit=sysop:move=sysop]

2021-02-03T09:23:11Z

Protected "7e0p" [edit=sysop:move=sysop]

←Older revision

Revision as of 09:23, 3 February 2021

OCA: New page: '''Unreleased structure''' The entry 7e0p is ON HOLD Authors: Li, G.-B., Ning, X.-L. Description: X-ray Structure-Guided Discovery of a Potent, Orally Bioavailable, Dual Human Indoleam...

2021-02-03T09:23:10Z

New page: '''Unreleased structure''' The entry 7e0p is ON HOLD Authors: Li, G.-B., Ning, X.-L. Description: X-ray Structure-Guided Discovery of a Potent, Orally Bioavailable, Dual Human Indoleam...

New page

'''Unreleased structure'''

The entry 7e0p is ON HOLD

Authors: Li, G.-B., Ning, X.-L.

Description: X-ray Structure-Guided Discovery of a Potent, Orally Bioavailable, Dual Human Indoleamine/Tryptophan 2,3-Dioxygenase (hIDO/hTDO) Inhibitor that Showed Activity in a Mouse Model of Parkinson's Diseases
[[Category: Unreleased Structures]]
[[Category: Li, G.-B]]
[[Category: Ning, X.-L]]