3o8a

<StructureSection load='3o8a' size='340' side='right' caption='[[3o8a]], [[Resolution|resolution]] 2.30&Aring;' scene=''>

<table><tr><td colspan='2'>[[3o8a]] 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=3O8A OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3O8A FirstGlance]. <br>

</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=FMN:FLAVIN+MONONUCLEOTIDE'>FMN</scene>, <scene name='pdbligand=LDA:LAURYL+DIMETHYLAMINE-N-OXIDE'>LDA</scene>, <scene name='pdbligand=O8A:N-CYCLOPROPYL-5-[2-METHYL-5-(TRIFLUOROMETHOXY)-1H-BENZIMIDAZOL-1-YL]THIOPHENE-2-CARBOXAMIDE'>O8A</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'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3o8a FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3o8a OCA], [http://pdbe.org/3o8a PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3o8a RCSB], [http://www.ebi.ac.uk/pdbsum/3o8a PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=3o8a ProSAT]</span></td></tr>

[[http://www.uniprot.org/uniprot/PYRD_PLAF7 PYRD_PLAF7]] Catalyzes the conversion of dihydroorotate to orotate with quinone as electron acceptor.

<scriptWhenChecked>select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/o8/3o8a_consurf.spt"</scriptWhenChecked>

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== Publication Abstract from PubMed ==

Plasmodium falciparum, the causative agent of the most deadly form of human malaria, is unable to salvage pyrimidines and must rely on de novo biosynthesis for survival. Dihydroorotate dehydrogenase (DHODH) catalyzes the rate-limiting step in the pyrimidine biosynthetic pathway and represents a potential target for anti-malarial therapy. A high throughput screen and subsequent medicinal chemistry program identified a series of N-alkyl-5-(1H-benzimidazol-1-yl)thiophene-2-carboxamides with low nanomolar in vitro potency against DHODH from P. falciparum, P. vivax, and P. berghei. The compounds were selective for the parasite enzymes over human DHODH, and x-ray structural data on the analog Genz-667348, demonstrated that species selectivity could be attributed to amino acid differences in the inhibitor-binding site. Compounds from this series demonstrated in vitro potency against the 3D7 and Dd2 strains of P. falciparum, good tolerability and oral exposure in the mouse, and ED(50) values in the 4-day murine P. berghei efficacy model of 13-21 mg/kg/day with oral twice-daily dosing. In particular, treatment with Genz-667348 at 100 mg/kg/day resulted in sterile cure. Two recent analogs of Genz-667348 are currently undergoing pilot toxicity testing to determine suitability as clinical development candidates.

 

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== References ==

[[Category: Plaf7]]

[[Category: Booker, M L]]

[[Category: Deng, X]]

[[Category: Phillips, M A]]

[[Category: Alpha beta fold]]

[[Category: Pyrimidine biosynthesis]]