5tpg

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==Optimization of spirocyclic proline tryptophanhydroxylase-1 inhibitors==
==Optimization of spirocyclic proline tryptophanhydroxylase-1 inhibitors==
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<StructureSection load='5tpg' size='340' side='right' caption='[[5tpg]], [[Resolution|resolution]] 1.50&Aring;' scene=''>
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<StructureSection load='5tpg' size='340' side='right'caption='[[5tpg]], [[Resolution|resolution]] 1.50&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>[[5tpg]] is a 1 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=5TPG OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5TPG FirstGlance]. <br>
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<table><tr><td colspan='2'>[[5tpg]] 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=5TPG OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5TPG FirstGlance]. <br>
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</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=7H5:(3S)-8-(2-AMINO-6-{(1R)-1-[5-CHLORO-3-(METHYLSULFONYL)[1,1-BIPHENYL]-2-YL]-2,2,2-TRIFLUOROETHOXY}PYRIMIDIN-4-YL)-2,8-DIAZASPIRO[4.5]DECANE-3-CARBOXYLIC+ACID'>7H5</scene>, <scene name='pdbligand=CCN:ACETONITRILE'>CCN</scene>, <scene name='pdbligand=FE:FE+(III)+ION'>FE</scene>, <scene name='pdbligand=TRS:2-AMINO-2-HYDROXYMETHYL-PROPANE-1,3-DIOL'>TRS</scene></td></tr>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.5&#8491;</td></tr>
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<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5l01|5l01]]</td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=7H5:(3S)-8-(2-AMINO-6-{(1R)-1-[5-CHLORO-3-(METHYLSULFONYL)[1,1-BIPHENYL]-2-YL]-2,2,2-TRIFLUOROETHOXY}PYRIMIDIN-4-YL)-2,8-DIAZASPIRO[4.5]DECANE-3-CARBOXYLIC+ACID'>7H5</scene>, <scene name='pdbligand=CCN:ACETONITRILE'>CCN</scene>, <scene name='pdbligand=FE:FE+(III)+ION'>FE</scene>, <scene name='pdbligand=TRS:2-AMINO-2-HYDROXYMETHYL-PROPANE-1,3-DIOL'>TRS</scene></td></tr>
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<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">TPH1, TPH, TPRH, TRPH ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=5tpg FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5tpg OCA], [https://pdbe.org/5tpg PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5tpg RCSB], [https://www.ebi.ac.uk/pdbsum/5tpg PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5tpg ProSAT]</span></td></tr>
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<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Tryptophan_5-monooxygenase Tryptophan 5-monooxygenase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.14.16.4 1.14.16.4] </span></td></tr>
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<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=5tpg FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5tpg OCA], [http://pdbe.org/5tpg PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5tpg RCSB], [http://www.ebi.ac.uk/pdbsum/5tpg PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5tpg ProSAT]</span></td></tr>
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</table>
</table>
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<div style="background-color:#fffaf0;">
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== Function ==
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== Publication Abstract from PubMed ==
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[https://www.uniprot.org/uniprot/TPH1_HUMAN TPH1_HUMAN]
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As a follow-up to the discovery of our spirocyclic proline-based TPH1 inhibitor lead, we describe the optimization of this scaffold. Through a combination of X-ray co-crystal structure guided design and an in vivo screen, new substitutions in the lipophilic region of the inhibitors were identified. This effort led to new TPH1 inhibitors with in vivo efficacy when dosed as their corresponding ethyl ester prodrugs. In particular, 15b (KAR5585), the prodrug of the potent TPH1 inhibitor 15a (KAR5417), showed robust reduction of intestinal serotonin (5-HT) levels in mice. Furthermore, oral administration of 15b generated high and sustained systemic exposure of the active parent 15a in rats and dogs. KAR5585 was selected for further pharmacological evaluation in disease models associated with a dysfunctional peripheral 5-HT system.
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Optimization of spirocyclic proline tryptophan hydroxylase-1 inhibitors.,Goldberg DR, De Lombaert S, Aiello R, Bourassa P, Barucci N, Zhang Q, Paralkar V, Stein AJ, Holt M, Valentine J, Zavadoski W Bioorg Med Chem Lett. 2017 Feb 1;27(3):413-419. doi: 10.1016/j.bmcl.2016.12.053. , Epub 2016 Dec 23. PMID:28041831<ref>PMID:28041831</ref>
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==See Also==
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*[[Hydroxylases 3D structures|Hydroxylases 3D structures]]
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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</div>
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<div class="pdbe-citations 5tpg" style="background-color:#fffaf0;"></div>
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== References ==
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<references/>
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__TOC__
__TOC__
</StructureSection>
</StructureSection>
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[[Category: Human]]
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[[Category: Homo sapiens]]
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[[Category: Tryptophan 5-monooxygenase]]
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[[Category: Large Structures]]
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[[Category: Goldberg, D R]]
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[[Category: De Lombaert S]]
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[[Category: Holt, M C]]
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[[Category: Goldberg DR]]
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[[Category: Lombaert, S De]]
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[[Category: Holt MC]]
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[[Category: Stein, A J]]
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[[Category: Stein AJ]]
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[[Category: Acyl]]
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[[Category: Iron]]
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[[Category: Oxidoreductase-inhibitor complex]]
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[[Category: Oxidoreductase-oxidoreductase inhibitor complex]]
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[[Category: Quanidine]]
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[[Category: Tph1]]
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Current revision

Optimization of spirocyclic proline tryptophanhydroxylase-1 inhibitors

PDB ID 5tpg

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