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3ara

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Revision as of 15:52, 4 October 2023

Discovery of Novel Uracil Derivatives as Potent Human dUTPase Inhibitors

Structural highlights

3ara is a 3 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 1.7Å
Ligands:	,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

DUT_HUMAN This enzyme is involved in nucleotide metabolism: it produces dUMP, the immediate precursor of thymidine nucleotides and it decreases the intracellular concentration of dUTP so that uracil cannot be incorporated into DNA.^[1]

Publication Abstract from PubMed

Recently, deoxyuridine triphosphatase (dUTPase) has emerged as a potential target for drug development as part of a new strategy of 5-fluorouracil-based combination chemotherapy. We have initiated a program to develop potent drug-like dUTPase inhibitors based on structure-activity relationship (SAR) studies of uracil derivatives. N-Carbonylpyrrolidine- and N-sulfonylpyrrolidine-containing uracils were found to be promising scaffolds that led us to human dUTPase inhibitors (12k) having excellent potencies (IC(50) = 0.15 muM). The X-ray structure of a complex of 16a and human dUTPase revealed a unique binding mode wherein its uracil ring and phenyl ring occupy a uracil recognition region and a hydrophobic region, respectively, and are stacked on each other. Compounds 12a and 16a markedly enhanced the growth inhibition activity of 5-fluoro-2'-deoxyuridine against HeLa S3 cells in vitro (EC(50) = 0.27-0.30 muM), suggesting that our novel dUTPase inhibitors could contribute to the development of chemotherapeutic strategies when used in combination with TS inhibitors.

Synthesis and discovery of N-carbonylpyrrolidine- or N-sulfonylpyrrolidine-containing uracil derivatives as potent human deoxyuridine triphosphatase inhibitors.,Miyakoshi H, Miyahara S, Yokogawa T, Chong KT, Taguchi J, Endoh K, Yano W, Wakasa T, Ueno H, Takao Y, Nomura M, Shuto S, Nagasawa H, Fukuoka M J Med Chem. 2012 Apr 12;55(7):2960-9. Epub 2012 Mar 26. PMID:22404301^[2]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Mol CD, Harris JM, McIntosh EM, Tainer JA. Human dUTP pyrophosphatase: uracil recognition by a beta hairpin and active sites formed by three separate subunits. Structure. 1996 Sep 15;4(9):1077-92. PMID:8805593
↑ Miyakoshi H, Miyahara S, Yokogawa T, Chong KT, Taguchi J, Endoh K, Yano W, Wakasa T, Ueno H, Takao Y, Nomura M, Shuto S, Nagasawa H, Fukuoka M. Synthesis and discovery of N-carbonylpyrrolidine- or N-sulfonylpyrrolidine-containing uracil derivatives as potent human deoxyuridine triphosphatase inhibitors. J Med Chem. 2012 Apr 12;55(7):2960-9. Epub 2012 Mar 26. PMID:22404301 doi:10.1021/jm201627n

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 See Also
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/3ara"

@@ Line 3: / Line 3: @@
 <StructureSection load='3ara' size='340' side='right'caption='[[3ara]], [[Resolution|resolution]] 1.70&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[3ara]] is a 3 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3ARA OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3ARA FirstGlance]. <br>
+<table><tr><td colspan='2'>[[3ara]] is a 3 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=3ARA OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3ARA FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=MKH:1-[3-({(2R)-2-[HYDROXY(DIPHENYL)METHYL]PYRROLIDIN-1-YL}SULFONYL)PROPYL]PYRIMIDINE-2,4(1H,3H)-DIONE'>MKH</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]] 1.7&#8491;</td></tr>
-<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[2hqu|2hqu]], [[3ehw|3ehw]], [[1q5h|1q5h]]</div></td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=MKH:1-[3-({(2R)-2-[HYDROXY(DIPHENYL)METHYL]PYRROLIDIN-1-YL}SULFONYL)PROPYL]PYRIMIDINE-2,4(1H,3H)-DIONE'>MKH</scene></td></tr>
-<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/dUTP_diphosphatase dUTP diphosphatase], with EC number [https://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.6.1.23 3.6.1.23] </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=3ara FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3ara OCA], [https://pdbe.org/3ara PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3ara RCSB], [https://www.ebi.ac.uk/pdbsum/3ara PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3ara ProSAT]</span></td></tr>
 </table>
 == Function ==
-[[https://www.uniprot.org/uniprot/DUT_HUMAN DUT_HUMAN]] This enzyme is involved in nucleotide metabolism: it produces dUMP, the immediate precursor of thymidine nucleotides and it decreases the intracellular concentration of dUTP so that uracil cannot be incorporated into DNA.<ref>PMID:8805593</ref>
+[https://www.uniprot.org/uniprot/DUT_HUMAN DUT_HUMAN] This enzyme is involved in nucleotide metabolism: it produces dUMP, the immediate precursor of thymidine nucleotides and it decreases the intracellular concentration of dUTP so that uracil cannot be incorporated into DNA.<ref>PMID:8805593</ref>
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
@@ Line 27: / Line 26: @@
 __TOC__
 </StructureSection>
-[[Category: Human]]
+[[Category: Homo sapiens]]
 [[Category: Large Structures]]
-[[Category: DUTP diphosphatase]]
+[[Category: Chong KT]]
-[[Category: Chong, K T]]
+[[Category: Fukuoka M]]
-[[Category: Fukuoka, M]]
+[[Category: Miyahara S]]
-[[Category: Miyahara, S]]
+[[Category: Miyakoshi H]]
-[[Category: Miyakoshi, H]]
-[[Category: Hydrolase]]
-[[Category: Hydrolase-hydrolase inhibitor complex]]
-[[Category: Magnesium binding]]

3ara

From Proteopedia

Revision as of 15:52, 4 October 2023

Discovery of Novel Uracil Derivatives as Potent Human dUTPase Inhibitors

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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