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| | <StructureSection load='6wjy' size='340' side='right'caption='[[6wjy]], [[Resolution|resolution]] 1.91Å' scene=''> | | <StructureSection load='6wjy' size='340' side='right'caption='[[6wjy]], [[Resolution|resolution]] 1.91Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[6wjy]] 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=6WJY OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6WJY FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[6wjy]] 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=6WJY OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6WJY FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=U41:3-chloro-N-(3-{(2S)-1-[(4-fluorophenyl)amino]-1-oxopropan-2-yl}bicyclo[1.1.1]pentan-1-yl)benzamide'>U41</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]] 1.91Å</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=U41:3-chloro-N-(3-{(2S)-1-[(4-fluorophenyl)amino]-1-oxopropan-2-yl}bicyclo[1.1.1]pentan-1-yl)benzamide'>U41</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=6wjy FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6wjy OCA], [https://pdbe.org/6wjy PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6wjy RCSB], [https://www.ebi.ac.uk/pdbsum/6wjy PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6wjy ProSAT]</span></td></tr> |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=6wjy FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6wjy OCA], [http://pdbe.org/6wjy PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6wjy RCSB], [http://www.ebi.ac.uk/pdbsum/6wjy PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6wjy 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;">
| + | |
| - | == Publication Abstract from PubMed ==
| + | |
| - | Indoleamine-2,3-dioxygenase 1 (IDO1) inhibition and its combination with immune checkpoint inhibitors like pembrolizumab have drawn considerable attention from both academia and the pharmaceutical industry. Here, we describe the discovery of a novel class of highly potent IDO1 heme-displacing inhibitors featuring a unique bicyclo[1.1.1]pentane motif. Compound 1, evolving from an ALIS (automated ligand identification system) hit, exhibited excellent potency but lacked the desired pharmacokinetic profile due to extensive amide hydrolysis of the benzamide moiety. Replacing the central phenyl ring in 1 with a bicyclo[1.1.1]pentane bioisostere effectively circumvented the amide hydrolysis issue, resulting in the discovery of compound 2 with a favorable overall profile such as excellent potency, selectivity, pharmacokinetics, and a low predicted human dose.
| + | |
| | | | |
| - | Discovery of Potent and Orally Available Bicyclo[1.1.1]pentane-Derived Indoleamine-2,3-dioxygenase 1 (IDO1) Inhibitors.,Pu Q, Zhang H, Guo L, Cheng M, Doty AC, Ferguson H, Fradera X, Lesburg CA, McGowan MA, Miller JR, Geda P, Song X, Otte K, Sciammetta N, Solban N, Yu W, Sloman DL, Zhou H, Lammens A, Neumann L, Bennett DJ, Pasternak A, Han Y ACS Med Chem Lett. 2020 Jul 15;11(8):1548-1554. doi:, 10.1021/acsmedchemlett.0c00195. eCollection 2020 Aug 13. PMID:32832022<ref>PMID:32832022</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 6wjy" 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: Neumann, L]] | + | [[Category: Neumann L]] |
| - | [[Category: Heme]]
| + | |
| - | [[Category: Indoleamine dioxygenase]]
| + | |
| - | [[Category: Inhibitor]]
| + | |
| - | [[Category: Oxidoreductase]]
| + | |
| - | [[Category: Oxidoreductase-oxidoreductase inhibitor complex]]
| + | |
