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PDBsum entry 4l6c
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Hydrolase/hydrolase inhibitor
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PDB id
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4l6c
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References listed in PDB file
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Key reference
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Title
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Conformationally constrained nucleoside phosphonic acids--Potent inhibitors of human mitochondrial and cytosolic 5'(3')-Nucleotidases.
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Authors
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O.ŠImák,
P.Pachl,
M.Fábry,
M.Buděšínský,
T.Jandušík,
A.Hnízda,
R.Skleničková,
M.Petrová,
V.Veverka,
P.ŘEzáčová,
J.Brynda,
I.Rosenberg.
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Ref.
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Org Biomol Chem, 2014,
12,
7971-7982.
[DOI no: ]
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PubMed id
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Abstract
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This work describes novel in vitro inhibitors of human mitochondrial (mdN) and
cytosolic (cdN) 5'(3')-deoxynucleotidases. We designed a series of derivatives
of the lead compound
(S)-1-[2-deoxy-3,5-O-(phosphonobenzylidene)-β-d-threo-pentofuranosyl]thymine
bearing various substituents in the para position of the benzylidene moiety.
Detailed kinetic study revealed that certain para substituents increase the
inhibitory potency (iodo derivative; K = 2.71 μM) and some induce a shift in
selectivity toward cdN (carboxy derivative, K = 11.60 μM; iodoxy derivative, K
= 6.60 μM). Crystal structures of mdN in complex with three of these compounds
revealed that various para substituents lead to two alternative inhibitor
binding modes within the enzyme active site. Two binding modes were also
identified for cdN complexes by heteronuclear NMR spectroscopy.
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