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PDBsum entry 4xzi
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Oxidoreductase
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PDB id
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4xzi
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References listed in PDB file
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Key reference
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Title
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Structural determinants of the selectivity of 3-Benzyluracil-1-Acetic acids toward human enzymes aldose reductase and akr1b10.
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Authors
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F.X.Ruiz,
A.Cousido-Siah,
S.Porté,
M.Domínguez,
I.Crespo,
C.Rechlin,
A.Mitschler,
..R.De lera,
M.J.Martín,
J...De la fuente,
G.Klebe,
X.Parés,
J.Farrés,
A.Podjarny.
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Ref.
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Chemmedchem, 2015,
10,
1989-2003.
[DOI no: ]
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PubMed id
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Abstract
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The human enzymes aldose reductase (AR) and AKR1B10 have been thoroughly
explored in terms of their roles in diabetes, inflammatory disorders, and
cancer. In this study we identified two new lead compounds,
2-(3-(4-chloro-3-nitrobenzyl)-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)acetic
acid (JF0048, 3) and
2-(2,4-dioxo-3-(2,3,4,5-tetrabromo-6-methoxybenzyl)-3,4-dihydropyrimidin-1(2H)-yl)acetic
acid (JF0049, 4), which selectively target these enzymes. Although 3 and 4 share
the 3-benzyluracil-1-acetic acid scaffold, they have different substituents in
their aryl moieties. Inhibition studies along with thermodynamic and structural
characterizations of both enzymes revealed that the chloronitrobenzyl moiety of
compound 3 can open the AR specificity pocket but not that of the AKR1B10
cognate. In contrast, the larger atoms at the ortho and/or meta positions of
compound 4 prevent the AR specificity pocket from opening due to steric
hindrance and provide a tighter fit to the AKR1B10 inhibitor binding pocket,
probably enhanced by the displacement of a disordered water molecule trapped in
a hydrophobic subpocket, creating an enthalpic signature. Furthermore, this
selectivity also occurs in the cell, which enables the development of a more
efficient drug design strategy: compound 3 prevents sorbitol accumulation in
human retinal ARPE-19 cells, whereas 4 stops proliferation in human lung cancer
NCI-H460 cells.
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