5cqz - Revision history

OCA at 10:05, 19 October 2016

OCA — Wed, 19 Oct 2016 10:05:23 GMT

←Older revision		Revision as of 10:05, 19 October 2016
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		+
	==Human cytosolic 5'-nucleotidase II in complex with 3-(3-Imidazol-1-ylphenyl)-N-(9H-purin-6-yl)benzamide==		==Human cytosolic 5'-nucleotidase II in complex with 3-(3-Imidazol-1-ylphenyl)-N-(9H-purin-6-yl)benzamide==
	<StructureSection load='5cqz' size='340' side='right' caption='[[5cqz]], [[Resolution\|resolution]] 2.90Å' scene=''>		<StructureSection load='5cqz' size='340' side='right' caption='[[5cqz]], [[Resolution\|resolution]] 2.90Å' scene=''>
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	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[4h4b\|4h4b]]</td></tr>		<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[4h4b\|4h4b]]</td></tr>
	<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/5'-nucleotidase 5'-nucleotidase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.1.3.5 3.1.3.5] </span></td></tr>		<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/5'-nucleotidase 5'-nucleotidase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.1.3.5 3.1.3.5] </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=5cqz FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5cqz OCA], [http://pdbe.org/5cqz PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5cqz RCSB], [http://www.ebi.ac.uk/pdbsum/5cqz PDBsum]</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=5cqz FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5cqz OCA], [http://pdbe.org/5cqz PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5cqz RCSB], [http://www.ebi.ac.uk/pdbsum/5cqz PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5cqz ProSAT]</span></td></tr>
	</table>		</table>
	== Disease ==		== Disease ==

OCA at 11:36, 30 December 2015

OCA — Wed, 30 Dec 2015 11:36:53 GMT

←Older revision		Revision as of 11:36, 30 December 2015
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	<div style="background-color:#fffaf0;">		<div style="background-color:#fffaf0;">
	== Publication Abstract from PubMed ==		== Publication Abstract from PubMed ==
-	~~Clinical~~ and ~~preclinical observations have lead~~ to the ~~hypothesis that~~ 5'-nucleotidase cN-II ~~could constitute a~~ therapeutic target in ~~oncology, either per se or to increase the activity of cytotoxic nucleoside analogs~~. ~~To identify potential cN-II inhibitors, we performed in silico screening~~ of ~~freely available chemical databases, in vitro enzymatic assays with recombinant cN-II, soaking experiments with crystals of truncated cN-II as well as biological evaluation of selected~~ compounds~~, alone or in combination with cytotoxic nucleoside analogs, on cancer cells. The top ranked compounds from virtual screening included an anthraquinone derivative~~ (~~AdiS~~) ~~that~~ were ~~shown to block the enzyme activity with a K(i) of 2.0mM. Soaking experiments performed with crystals of truncated~~ cN-II ~~allowed to obtain crystallographic data at~~ a ~~resolution~~ of ~~2.9A and indicating interaction between AdiS and F354/I152 situated~~ in the ~~effector site 1 of cN-II~~. ~~In addition, this compound exhibited different levels of cytotoxicity~~ in ~~vitro on several~~ cancer cell lines ~~and increased the induction of apoptosis in RL cells incubated with 0.5 or 1.5muM cladribine, 0.05muM clofarabine or 30muM fludarabine. Finally, AdiS~~ showed ~~synergy~~ with ~~cladribine and additivity with clofarabine~~. ~~This study showed that virtual screening is a useful tool for~~ the identification of ~~potent~~ cN-II ~~inhibitors, and our biological results indicated interesting activity for one lead compound~~ that ~~can be further developed as therapeutics~~.	+	We used a combined approach based on fragment-based drug design (FBDD) and in silico methods to design potential inhibitors of the cytosolic 5'-nucleotidase II (cN-II), which has been recognized as an important therapeutic target in hematological cancers. Two subgroups of small compounds (including adenine and biaryl moieties) were identified as cN-II binders and a fragment growing strategy guided by molecular docking was considered. Five compounds induced a strong inhibition of the 5'-nucleotidase activity in vitro, and the most potent ones were characterized as noncompetitive inhibitors. Biological evaluation in cancer cell lines showed synergic effect with selected anticancer drugs. Structural studies using X-ray crystallography lead to the identification of new binding sites for two derivatives and of a new crystal form showing important domain swapping. Altogether, the strategy developed herein allowed identifying new original noncompetitive inhibitors against cN-II that act in a synergistic manner with well-known antitumoral agents.

-	Identification ~~and characterization~~ of ~~inhibitors~~ of ~~cytoplasmic~~ 5'-~~nucleotidase cN-~~II ~~issued from virtual screening~~.,Jordheim LP, ~~Marton Z~~, ~~Rhimi M~~, ~~Cros-Perrial E~~, Lionne C, Peyrottes S~~, Dumontet C, Aghajari N~~, Chaloin L ~~Biochem Pharmacol~~. ~~2012~~ Dec ~~7. pii: S0006-2952~~(12)~~00765~~-4. doi:, 10.~~1016~~/j.~~bcp~~.~~2012~~.~~11.024~~. PMID:~~23220537~~<ref>PMID:~~23220537~~</ref>	+	Identification of Noncompetitive Inhibitors of Cytosolic 5'-Nucleotidase II Using a Fragment-Based Approach.,Marton Z, Guillon R, Krimm I, Preeti, Rahimova R, Egron D, Jordheim LP, Aghajari N, Dumontet C, Perigaud C, Lionne C, Peyrottes S, Chaloin L J Med Chem. 2015 Dec 24;58(24):9680-96. doi: 10.1021/acs.jmedchem.5b01616. Epub, 2015 Dec 7. PMID:26599519<ref>PMID:26599519</ref>

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

OCA at 12:41, 23 December 2015

OCA — Wed, 23 Dec 2015 12:41:28 GMT

←Older revision		Revision as of 12:41, 23 December 2015
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-	'''~~Unreleased~~ structure'''	+	==Human cytosolic 5'-nucleotidase II in complex with 3-(3-Imidazol-1-ylphenyl)-N-(9H-purin-6-yl)benzamide==
		+	<StructureSection load='5cqz' size='340' side='right' caption='[[5cqz]], [[Resolution\|resolution]] 2.90Å' scene=''>
		+	== Structural highlights ==
		+	<table><tr><td colspan='2'>[[5cqz]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5CQZ OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5CQZ FirstGlance]. <br>
		+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=53O:1-(BIPHENYL-3-YL)-1H-IMIDAZOLE'>53O</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
		+	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[4h4b\|4h4b]]</td></tr>
		+	<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/5'-nucleotidase 5'-nucleotidase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.1.3.5 3.1.3.5] </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=5cqz FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5cqz OCA], [http://pdbe.org/5cqz PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5cqz RCSB], [http://www.ebi.ac.uk/pdbsum/5cqz PDBsum]</span></td></tr>
		+	</table>
		+	== Disease ==
		+	[[http://www.uniprot.org/uniprot/5NTC_HUMAN 5NTC_HUMAN]] Autosomal recessive spastic paraplegia type 45. The disease is caused by mutations affecting the gene represented in this entry.<ref>PMID:24482476</ref>
		+	== Function ==
		+	[[http://www.uniprot.org/uniprot/5NTC_HUMAN 5NTC_HUMAN]] May have a critical role in the maintenance of a constant composition of intracellular purine/pyrimidine nucleotides in cooperation with other nucleotidases. Preferentially hydrolyzes inosine 5'-monophosphate (IMP) and other purine nucleotides.
		+	<div style="background-color:#fffaf0;">
		+	== Publication Abstract from PubMed ==
		+	Clinical and preclinical observations have lead to the hypothesis that 5'-nucleotidase cN-II could constitute a therapeutic target in oncology, either per se or to increase the activity of cytotoxic nucleoside analogs. To identify potential cN-II inhibitors, we performed in silico screening of freely available chemical databases, in vitro enzymatic assays with recombinant cN-II, soaking experiments with crystals of truncated cN-II as well as biological evaluation of selected compounds, alone or in combination with cytotoxic nucleoside analogs, on cancer cells. The top ranked compounds from virtual screening included an anthraquinone derivative (AdiS) that were shown to block the enzyme activity with a K(i) of 2.0mM. Soaking experiments performed with crystals of truncated cN-II allowed to obtain crystallographic data at a resolution of 2.9A and indicating interaction between AdiS and F354/I152 situated in the effector site 1 of cN-II. In addition, this compound exhibited different levels of cytotoxicity in vitro on several cancer cell lines and increased the induction of apoptosis in RL cells incubated with 0.5 or 1.5muM cladribine, 0.05muM clofarabine or 30muM fludarabine. Finally, AdiS showed synergy with cladribine and additivity with clofarabine. This study showed that virtual screening is a useful tool for the identification of potent cN-II inhibitors, and our biological results indicated interesting activity for one lead compound that can be further developed as therapeutics.

-	~~The entry 5cqz is ON HOLD~~	+	Identification and characterization of inhibitors of cytoplasmic 5'-nucleotidase cN-II issued from virtual screening.,Jordheim LP, Marton Z, Rhimi M, Cros-Perrial E, Lionne C, Peyrottes S, Dumontet C, Aghajari N, Chaloin L Biochem Pharmacol. 2012 Dec 7. pii: S0006-2952(12)00765-4. doi:, 10.1016/j.bcp.2012.11.024. PMID:23220537<ref>PMID:23220537</ref>

-	~~Authors: Preeti~~, P.~~, Aghajari, N~~.	+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-		+	</div>
-	~~Description~~: ~~Human cytosolic~~ 5'-nucleotidase ~~II in complex with 3-(3-Imidazol-1-ylphenyl)-N-(9H-purin-6-yl)benzamide~~	+	<div class="pdbe-citations 5cqz" style="background-color:#fffaf0;"></div>
-	[[Category: ~~Unreleased Structures~~]]	+	== References ==
		+	<references/>
		+	__TOC__
		+	</StructureSection>
		+	[[Category: 5'-nucleotidase]]
		+	[[Category: Aghajari, N]]
	[[Category: Preeti, P]]		[[Category: Preeti, P]]
-	[[Category: ~~Aghajari, N~~]]	+	[[Category: Cn-ii]]
		+	[[Category: High km 5-prime nucleotidase]]
		+	[[Category: Hydrolase]]
		+	[[Category: Hydrolase-hydrolase effector complex]]
		+	[[Category: Nucleotide-binding]]
		+	[[Category: Phosphoprotein]]

OCA: Protected "5cqz" [edit=sysop:move=sysop]

OCA — Wed, 29 Jul 2015 13:45:53 GMT

Protected "5cqz" [edit=sysop:move=sysop]

←Older revision

Revision as of 13:45, 29 July 2015

OCA: New page: '''Unreleased structure''' The entry 5cqz is ON HOLD Authors: Preeti, P., Aghajari, N. Description: Human cytosolic 5'-nucleotidase II in complex with 3-(3-Imidazol-1-ylphenyl)-N-(9H-p...

OCA — Wed, 29 Jul 2015 13:45:52 GMT

New page: '''Unreleased structure''' The entry 5cqz is ON HOLD Authors: Preeti, P., Aghajari, N. Description: Human cytosolic 5'-nucleotidase II in complex with 3-(3-Imidazol-1-ylphenyl)-N-(9H-p...

New page

'''Unreleased structure'''

The entry 5cqz is ON HOLD

Authors: Preeti, P., Aghajari, N.

Description: Human cytosolic 5'-nucleotidase II in complex with 3-(3-Imidazol-1-ylphenyl)-N-(9H-purin-6-yl)benzamide
[[Category: Unreleased Structures]]
[[Category: Preeti, P]]
[[Category: Aghajari, N]]