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| | <StructureSection load='5fi8' size='340' side='right'caption='[[5fi8]], [[Resolution|resolution]] 2.32Å' scene=''> | | <StructureSection load='5fi8' size='340' side='right'caption='[[5fi8]], [[Resolution|resolution]] 2.32Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5fi8]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Plaf7 Plaf7]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5FI8 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5FI8 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5fi8]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Plasmodium_falciparum_3D7 Plasmodium falciparum 3D7]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5FI8 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5FI8 FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=5Y5:2-[1,1-BIS(FLUORANYL)ETHYL]-~{N}-[(2~{S})-7-BROMANYL-1,2,3,4-TETRAHYDRONAPHTHALEN-2-YL]-5-METHYL-[1,2,4]TRIAZOLO[1,5-A]PYRIMIDIN-7-AMINE'>5Y5</scene>, <scene name='pdbligand=FMN:FLAVIN+MONONUCLEOTIDE'>FMN</scene>, <scene name='pdbligand=LDA:LAURYL+DIMETHYLAMINE-N-OXIDE'>LDA</scene>, <scene name='pdbligand=ORO:OROTIC+ACID'>ORO</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]] 2.32Å</td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">PFF0160c ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=36329 PLAF7])</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=5Y5:2-[1,1-BIS(FLUORANYL)ETHYL]-~{N}-[(2~{S})-7-BROMANYL-1,2,3,4-TETRAHYDRONAPHTHALEN-2-YL]-5-METHYL-[1,2,4]TRIAZOLO[1,5-A]PYRIMIDIN-7-AMINE'>5Y5</scene>, <scene name='pdbligand=FMN:FLAVIN+MONONUCLEOTIDE'>FMN</scene>, <scene name='pdbligand=LDA:LAURYL+DIMETHYLAMINE-N-OXIDE'>LDA</scene>, <scene name='pdbligand=ORO:OROTIC+ACID'>ORO</scene></td></tr> |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Dihydroorotate_dehydrogenase_(quinone) Dihydroorotate dehydrogenase (quinone)], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.3.5.2 1.3.5.2] </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=5fi8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5fi8 OCA], [https://pdbe.org/5fi8 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5fi8 RCSB], [https://www.ebi.ac.uk/pdbsum/5fi8 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5fi8 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=5fi8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5fi8 OCA], [http://pdbe.org/5fi8 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5fi8 RCSB], [http://www.ebi.ac.uk/pdbsum/5fi8 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5fi8 ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/PYRD_PLAF7 PYRD_PLAF7]] Catalyzes the conversion of dihydroorotate to orotate with quinone as electron acceptor. | + | [https://www.uniprot.org/uniprot/PYRD_PLAF7 PYRD_PLAF7] Catalyzes the conversion of dihydroorotate to orotate with quinone as electron acceptor. |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | </StructureSection> | | </StructureSection> |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Plaf7]] | + | [[Category: Plasmodium falciparum 3D7]] |
| - | [[Category: Deng, X]] | + | [[Category: Deng X]] |
| - | [[Category: Kokkonda, S]] | + | [[Category: Kokkonda S]] |
| - | [[Category: Phillips, M]] | + | [[Category: Phillips M]] |
| - | [[Category: Tomchick, D]] | + | [[Category: Tomchick D]] |
| - | [[Category: Alpha/beta barrel]]
| + | |
| - | [[Category: Fmn]]
| + | |
| - | [[Category: Inhibitor]]
| + | |
| - | [[Category: Oxidoreductase / oxidoreductase]]
| + | |
| - | [[Category: Oxidoreductase-oxidoreductase inhibitor complex]]
| + | |
| Structural highlights
Function
PYRD_PLAF7 Catalyzes the conversion of dihydroorotate to orotate with quinone as electron acceptor.
Publication Abstract from PubMed
Malaria persists as one of the most devastating global infectious diseases. The pyrimidine biosynthetic enzyme dihydroorotate dehydrogenase (DHODH) has been identified as a new malaria drug target, and a triazolopyrimidine-based DHODH inhibitor 1 (DSM265) is in clinical development. We sought to identify compounds with higher potency against Plasmodium DHODH while showing greater selectivity toward animal DHODHs. Herein we describe a series of novel triazolopyrimidines wherein the p-SF5-aniline was replaced with substituted 1,2,3,4-tetrahydro-2-naphthyl or 2-indanyl amines. These compounds showed strong species selectivity, and several highly potent tetrahydro-2-naphthyl derivatives were identified. Compounds with halogen substitutions displayed sustained plasma levels after oral dosing in rodents leading to efficacy in the P. falciparum SCID mouse malaria model. These data suggest that tetrahydro-2-naphthyl derivatives have the potential to be efficacious for the treatment of malaria, but due to higher metabolic clearance than 1, they most likely would need to be part of a multidose regimen.
Tetrahydro-2-naphthyl and 2-Indanyl Triazolopyrimidines Targeting Plasmodium falciparum Dihydroorotate Dehydrogenase Display Potent and Selective Antimalarial Activity.,Kokkonda S, Deng X, White KL, Coteron JM, Marco M, de Las Heras L, White J, El Mazouni F, Tomchick DR, Manjalanagara K, Rudra KR, Chen G, Morizzi J, Ryan E, Kaminsky W, Leroy D, Martinez-Martinez MS, Jimenez-Diaz MB, Bazaga SF, Angulo-Barturen I, Waterson D, Burrows JN, Matthews D, Charman SA, Phillips MA, Rathod PK J Med Chem. 2016 May 21. PMID:27127993[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Kokkonda S, Deng X, White KL, Coteron JM, Marco M, de Las Heras L, White J, El Mazouni F, Tomchick DR, Manjalanagara K, Rudra KR, Chen G, Morizzi J, Ryan E, Kaminsky W, Leroy D, Martinez-Martinez MS, Jimenez-Diaz MB, Bazaga SF, Angulo-Barturen I, Waterson D, Burrows JN, Matthews D, Charman SA, Phillips MA, Rathod PK. Tetrahydro-2-naphthyl and 2-Indanyl Triazolopyrimidines Targeting Plasmodium falciparum Dihydroorotate Dehydrogenase Display Potent and Selective Antimalarial Activity. J Med Chem. 2016 May 21. PMID:27127993 doi:http://dx.doi.org/10.1021/acs.jmedchem.6b00275
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