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| | <StructureSection load='6wpe' size='340' side='right'caption='[[6wpe]], [[Resolution|resolution]] 2.43Å' scene=''> | | <StructureSection load='6wpe' size='340' side='right'caption='[[6wpe]], [[Resolution|resolution]] 2.43Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[6wpe]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6WPE OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6WPE FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[6wpe]] 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=6WPE OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6WPE FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=U6G:4-chloro-N-{[1-(3-chlorobenzene-1-carbonyl)-1,2,3,4-tetrahydroquinolin-6-yl]methyl}benzamide'>U6G</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]] 2.43Å</td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">IDO1, IDO, INDO ([https://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=U6G:4-chloro-N-{[1-(3-chlorobenzene-1-carbonyl)-1,2,3,4-tetrahydroquinolin-6-yl]methyl}benzamide'>U6G</scene></td></tr> |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Indoleamine_2,3-dioxygenase Indoleamine 2,3-dioxygenase], with EC number [https://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=6wpe FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6wpe OCA], [https://pdbe.org/6wpe PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6wpe RCSB], [https://www.ebi.ac.uk/pdbsum/6wpe PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6wpe 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=6wpe FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6wpe OCA], [https://pdbe.org/6wpe PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6wpe RCSB], [https://www.ebi.ac.uk/pdbsum/6wpe PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6wpe ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Function == | | == 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>
| + | [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 ==
| + | |
| - | Indoleamine-2,3-dioxygenase-1 (IDO1) has emerged as an attractive target for cancer immunotherapy. An automated ligand identification system screen afforded the tetrahydroquinoline class of novel IDO1 inhibitors. Potency and pharmacokinetic (PK) were key issues with this class of compounds. Structure-based drug design and strategic incorporation of polarity enabled the rapid improvement on potency, solubility, and oxidative metabolic stability. Metabolite identification studies revealed that amide hydrolysis in the D-pocket was the key clearance mechanism for this class. Strategic survey of amide isosteres revealed that carbamates and N-pyrimidines, which maintained exquisite potencies, mitigated the amide hydrolysis issue and led to an improved rat PK profile. The lead compound 28 is a potent IDO1 inhibitor, with clean off-target profiles and the potential for quaque die dosing in humans.
| + | |
| | | | |
| - | Carbamate and N-Pyrimidine Mitigate Amide Hydrolysis: Structure-Based Drug Design of Tetrahydroquinoline IDO1 Inhibitors.,Li D, Deng Y, Achab A, Bharathan I, Hopkins BA, Yu W, Zhang H, Sanyal S, Pu Q, Zhou H, Liu K, Lim J, Fradera X, Lesburg CA, Lammens A, Martinot TA, Cohen RD, Doty AC, Ferguson H, Nickbarg EB, Cheng M, Spacciapoli P, Geda P, Song X, Smotrov N, Abeywickrema P, Andrews C, Chamberlin C, Mabrouk O, Curran P, Richards M, Saradjian P, Miller JR, Knemeyer I, Otte KM, Vincent S, Sciammetta N, Pasternak A, Bennett DJ, Han Y ACS Med Chem Lett. 2021 Feb 26;12(3):389-396. doi:, 10.1021/acsmedchemlett.0c00525. eCollection 2021 Mar 11. PMID:33738066<ref>PMID:33738066</ref>
| + | ==See Also== |
| - | | + | *[[Dioxygenase 3D structures|Dioxygenase 3D structures]] |
| - | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
| + | |
| - | </div>
| + | |
| - | <div class="pdbe-citations 6wpe" style="background-color:#fffaf0;"></div>
| + | |
| | == 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: Lammens, A]] | + | [[Category: Lammens A]] |
| - | [[Category: Lesburg, C A]] | + | [[Category: Lesburg CA]] |
| - | [[Category: Heme]]
| + | |
| - | [[Category: Indoleamine dioxygenase]]
| + | |
| - | [[Category: Inhibitor]]
| + | |
| - | [[Category: Oxidoreductase]]
| + | |
| - | [[Category: Oxidoreductase-oxidoreductase inhibitor complex]]
| + | |
