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PDBsum entry 4k5h
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Oxidoreductase/oxidoreductase inhibitor
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PDB id
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4k5h
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References listed in PDB file
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Key reference
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Title
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Chiral linkers to improve selectivity of double-Headed neuronal nitric oxide synthase inhibitors.
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Authors
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Q.Jing,
H.Li,
G.Chreifi,
L.J.Roman,
P.Martásek,
T.L.Poulos,
R.B.Silverman.
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Ref.
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Bioorg Med Chem Lett, 2013,
23,
5674-5679.
[DOI no: ]
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PubMed id
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Abstract
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To develop potent and selective nNOS inhibitors, new double-headed molecules
with chiral linkers that derive from natural amino acids or their derivatives
have been designed. The new structures contain two ether bonds, which greatly
simplifies the synthesis and accelerates structure optimization. Inhibitor
(R)-6b exhibits a potency of 32nM against nNOS and is 475 and 244 more selective
for nNOS over eNOS and iNOS, respectively. Crystal structures show that the
additional binding between the aminomethyl moiety of 6b and the two heme
propionates in nNOS, but not eNOS, is the structural basis for its high
selectivity. This work demonstrates the importance of stereochemistry in this
class of molecules, which significantly influences the potency and selectivity
of the inhibitors. The structure-activity information gathered here provides a
guide for future structure optimization.
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