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| | <StructureSection load='6o3i' size='340' side='right'caption='[[6o3i]], [[Resolution|resolution]] 2.69Å' scene=''> | | <StructureSection load='6o3i' size='340' side='right'caption='[[6o3i]], [[Resolution|resolution]] 2.69Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[6o3i]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6O3I OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6O3I FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[6o3i]] 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=6O3I OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6O3I FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=HEM:PROTOPORPHYRIN+IX+CONTAINING+FE'>HEM</scene>, <scene name='pdbligand=LKP:trans-4-{(1R)-2-[(5S)-6-fluoro-5H-imidazo[5,1-a]isoindol-5-yl]-1-hydroxyethyl}cyclohexan-1-ol'>LKP</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]] 2.69Å</td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">IDO1, IDO, INDO ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=HEM:PROTOPORPHYRIN+IX+CONTAINING+FE'>HEM</scene>, <scene name='pdbligand=LKP:4-[(1~{R})-2-[(5~{S})-6-fluoranyl-5~{H}-imidazo[1,5-b]isoindol-5-yl]-1-oxidanyl-ethyl]cyclohexan-1-ol'>LKP</scene></td></tr> |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Indoleamine_2,3-dioxygenase Indoleamine 2,3-dioxygenase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.13.11.52 1.13.11.52] </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=6o3i FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6o3i OCA], [https://pdbe.org/6o3i PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6o3i RCSB], [https://www.ebi.ac.uk/pdbsum/6o3i PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6o3i ProSAT]</span></td></tr> |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6o3i FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6o3i OCA], [http://pdbe.org/6o3i PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6o3i RCSB], [http://www.ebi.ac.uk/pdbsum/6o3i PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6o3i ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://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> | + | [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;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | </div> | | </div> |
| | <div class="pdbe-citations 6o3i" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 6o3i" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[Dioxygenase 3D structures|Dioxygenase 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Indoleamine 2,3-dioxygenase]]
| + | |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Harris, S F]] | + | [[Category: Harris SF]] |
| - | [[Category: Oh, A]] | + | [[Category: Oh A]] |
| - | [[Category: Dioxygenase]]
| + | |
| - | [[Category: Ido]]
| + | |
| - | [[Category: Oxidoreductase-inhibitor complex]]
| + | |
| - | [[Category: Tdo]]
| + | |
| - | [[Category: Tryptophan]]
| + | |
| Structural highlights
Function
I23O1_HUMAN Catalyzes the cleavage of the pyrrol ring of tryptophan and incorporates both atoms of a molecule of oxygen.[1]
Publication Abstract from PubMed
A novel class of 5-substituted 5 H-imidazo[5,1- a]isoindoles are described as potent inhibitors of indoleamine 2,3-dioxygenase 1 (IDO1). A structure-based drug design approach was used to elaborate the 5 H-imidazo[5,1- a]isoindole core and to improve potency and pharmacological properties. Suitably placed hydrophobic and polar functional groups in the lead molecule allowed improvement of IDO1 inhibitory activity while minimizing off-target liabilities. Structure-activity relationship studies focused on optimizing IDO1 inhibition potency and a pharmacokinetic profile amenable to oral dosing while controlling CYP450 and hERG inhibitory properties.
Discovery of Clinical Candidate (1 R,4 r)-4-(( R)-2-(( S)-6-Fluoro-5 H-imidazo[5,1- a]isoindol-5-yl)-1-hydroxyethyl)cyclohexan-1-ol (Navoximod), a Potent and Selective Inhibitor of Indoleamine 2,3-Dioxygenase 1.,Kumar S, Waldo JP, Jaipuri FA, Marcinowicz A, Van Allen C, Adams J, Kesharwani T, Zhang X, Metz R, Oh AJ, Harris SF, Mautino MR J Med Chem. 2019 Jul 2. doi: 10.1021/acs.jmedchem.9b00662. PMID:31264862[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Metz R, Duhadaway JB, Kamasani U, Laury-Kleintop L, Muller AJ, Prendergast GC. Novel tryptophan catabolic enzyme IDO2 is the preferred biochemical target of the antitumor indoleamine 2,3-dioxygenase inhibitory compound D-1-methyl-tryptophan. Cancer Res. 2007 Aug 1;67(15):7082-7. PMID:17671174 doi:http://dx.doi.org/10.1158/0008-5472.CAN-07-1872
- ↑ Kumar S, Waldo JP, Jaipuri FA, Marcinowicz A, Van Allen C, Adams J, Kesharwani T, Zhang X, Metz R, Oh AJ, Harris SF, Mautino MR. Discovery of Clinical Candidate (1 R,4 r)-4-(( R)-2-(( S)-6-Fluoro-5 H-imidazo[5,1- a]isoindol-5-yl)-1-hydroxyethyl)cyclohexan-1-ol (Navoximod), a Potent and Selective Inhibitor of Indoleamine 2,3-Dioxygenase 1. J Med Chem. 2019 Jul 2. doi: 10.1021/acs.jmedchem.9b00662. PMID:31264862 doi:http://dx.doi.org/10.1021/acs.jmedchem.9b00662
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