6n1t
From Proteopedia
(Difference between revisions)
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| - | '''Unreleased structure''' | ||
| - | + | ==Toxoplasma gondii TS-DHFR in complex with selective inhibitor 3== | |
| + | <StructureSection load='6n1t' size='340' side='right'caption='[[6n1t]], [[Resolution|resolution]] 3.50Å' scene=''> | ||
| + | == Structural highlights == | ||
| + | <table><tr><td colspan='2'>[[6n1t]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Toxgo Toxgo]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6N1T OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6N1T FirstGlance]. <br> | ||
| + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=BOD:5-{4-[3-(2-methoxypyrimidin-5-yl)phenyl]piperazin-1-yl}pyrimidine-2,4-diamine'>BOD</scene>, <scene name='pdbligand=CB3:10-PROPARGYL-5,8-DIDEAZAFOLIC+ACID'>CB3</scene>, <scene name='pdbligand=NDP:NADPH+DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NDP</scene>, <scene name='pdbligand=UMP:2-DEOXYURIDINE+5-MONOPHOSPHATE'>UMP</scene></td></tr> | ||
| + | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4eil|4eil]], [[6aog|6aog]], [[6aoh|6aoh]], [[6aoi|6aoi]], [[6n1s|6n1s]]</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=6n1t FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6n1t OCA], [http://pdbe.org/6n1t PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6n1t RCSB], [http://www.ebi.ac.uk/pdbsum/6n1t PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6n1t ProSAT]</span></td></tr> | ||
| + | </table> | ||
| + | == Function == | ||
| + | [[http://www.uniprot.org/uniprot/DRTS_TOXGO DRTS_TOXGO]] Bifunctional enzyme. Involved in de novo dTMP biosynthesis. Key enzyme in folate metabolism. Catalyzes an essential reaction for de novo glycine and purine synthesis, DNA precursor synthesis, and for the conversion of dUMP to dTMP (By similarity). | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | A safer treatment for toxoplasmosis would be achieved by improving the selectivity and potency of dihydrofolate reductase (DHFR) inhibitors, such as pyrimethamine (1), for Toxoplasma gondii DHFR ( TgDHFR) relative to human DHFR ( hDHFR). We previously reported on the identification of meta-biphenyl analog 2, designed by in silico modeling of key differences in the binding pocket between TgDHFR and hDHFR. Compound 2 improves TgDHFR selectivity 6.6-fold and potency 16-fold relative to 1. Here, we report on the optimization and structure-activity relationships of this arylpiperazine series leading to the discovery of 5-(4-(3-(2-methoxypyrimidin-5-yl)phenyl)piperazin-1-yl)pyrimidine-2,4-diamine 3. Compound 3 has a TgDHFR IC50 of 1.57 +/- 0.11 nM and a hDHFR to TgDHFR selectivity ratio of 196, making it 89-fold more potent and 16-fold more selective than 1. Compound 3 was highly effective in control of acute infection by highly virulent strains of T. gondii in the murine model, and it possesses the best combination of selectivity, potency, and prerequisite drug-like properties to advance into IND-enabling, preclinical development. | ||
| - | + | Discovery of Selective Toxoplasma gondii Dihydrofolate Reductase Inhibitors for the Treatment of Toxoplasmosis.,Hopper AT, Brockman A, Wise A, Gould J, Barks J, Radke JB, Sibley LD, Zou Y, Thomas S J Med Chem. 2019 Feb 14;62(3):1562-1576. doi: 10.1021/acs.jmedchem.8b01754. Epub , 2019 Jan 24. PMID:30624926<ref>PMID:30624926</ref> | |
| - | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| - | + | </div> | |
| - | + | <div class="pdbe-citations 6n1t" style="background-color:#fffaf0;"></div> | |
| - | + | == References == | |
| - | + | <references/> | |
| - | + | __TOC__ | |
| - | + | </StructureSection> | |
| - | [[Category: | + | [[Category: Large Structures]] |
| - | [[Category: | + | [[Category: Toxgo]] |
[[Category: Barks, J]] | [[Category: Barks, J]] | ||
[[Category: Brockman, A]] | [[Category: Brockman, A]] | ||
| + | [[Category: Gould, J]] | ||
| + | [[Category: Hopper, A T]] | ||
| + | [[Category: Radke, J B]] | ||
| + | [[Category: Sibley, L D]] | ||
| + | [[Category: Thomas, S B]] | ||
| + | [[Category: Wise, A]] | ||
| + | [[Category: Zou, Y]] | ||
| + | [[Category: Dhfr]] | ||
| + | [[Category: Oxidoreductase]] | ||
| + | [[Category: Oxidoreductase-oxidoreductase inhibitor complex]] | ||
| + | [[Category: Toxoplasma gondii]] | ||
Revision as of 08:16, 24 April 2019
Toxoplasma gondii TS-DHFR in complex with selective inhibitor 3
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