View source for 5ou0


==Crystal structure of human AKR1B1 complexed with NADP+ and compound 37==
<StructureSection load='5ou0' size='340' side='right'caption='[[5ou0]], [[Resolution|resolution]] 0.94&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[5ou0]] is a 1 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=5OU0 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5OU0 FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 0.94&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=AV5:2-[5-(4-chlorophenyl)-3-methyl-1-oxidanylidene-pyrimido[4,5-c]quinolin-2-yl]ethanoic+acid'>AV5</scene>, <scene name='pdbligand=NAP:NADP+NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NAP</scene></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=5ou0 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5ou0 OCA], [https://pdbe.org/5ou0 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5ou0 RCSB], [https://www.ebi.ac.uk/pdbsum/5ou0 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5ou0 ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/ALDR_HUMAN ALDR_HUMAN] Catalyzes the NADPH-dependent reduction of a wide variety of carbonyl-containing compounds to their corresponding alcohols with a broad range of catalytic efficiencies.
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Human aldose reductase (AKR1B1, AR) is a key enzyme of the polyol pathway, catalyzing the reduction of glucose to sorbitol at high glucose concentrations, as those found in diabetic condition. Indeed, AKR1B1 overexpression is related to diabetes secondary complications and, in some cases, with cancer. For many years, research has been focused on finding new AKR1B1 inhibitors (ARIs) to overcome these diseases. Despite the efforts, most of the new drug candidates failed because of their poor pharmacokinetic properties and/or unacceptable side effects. Here we report the synthesis of a series of 1-oxopyrimido[4,5-c]quinoline-2-acetic acid derivatives as novel ARIs. IC50 assays and X-ray crystallographic studies proved that these compounds are promising hits for further drug development, with high potency and selectivity against AKR1B1. Based on the determined X-ray structures with hit-to-lead compounds, we designed and synthesized a second series that yielded lead compound 68 (Ki(app)vs. AKR1B1=73nM). These compounds are related to the previously reported 2-aminopyrimido[4,5-c]quinolin-1(2H)-ones, which exhibit antimitotic activity. Regardless of their similarity, the 2-amino compounds are unable to inhibit AKR1B1 while the 2-acetic acid derivatives are not cytotoxic against fibrosarcoma HT-1080cells. Thus, the replacement of the amino group by an acetic acid moiety changes their biological activity, improving their potency as ARIs.

Design, synthesis, structure-activity relationships and X-ray structural studies of novel 1-oxopyrimido[4,5-c]quinoline-2-acetic acid derivatives as selective and potent inhibitors of human aldose reductase.,Crespo I, Gimenez-Dejoz J, Porte S, Cousido-Siah A, Mitschler A, Podjarny A, Pratsinis H, Kletsas D, Pares X, Ruiz FX, Metwally K, Farres J Eur J Med Chem. 2018 Apr 12;152:160-174. doi: 10.1016/j.ejmech.2018.04.015. PMID:29705708<ref>PMID:29705708</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 5ou0" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Cousido-Siah A]]
[[Category: Metwally K]]
[[Category: Mitschler A]]
[[Category: Podjarny A]]
[[Category: Ruiz FX]]