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PDBsum entry 4imx
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Oxidoreductase/oxidoreductase inhibitor
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PDB id
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4imx
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References listed in PDB file
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Key reference
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Title
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Structure-Guided design of selective inhibitors of neuronal nitric oxide synthase.
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Authors
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H.Huang,
H.Li,
P.Martásek,
L.J.Roman,
T.L.Poulos,
R.B.Silverman.
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Ref.
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J Med Chem, 2013,
56,
3024-3032.
[DOI no: ]
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PubMed id
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Abstract
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Nitric oxide synthases (NOSs) comprise three closely related isoforms that
catalyze the oxidation of l-arginine to l-citrulline and the important second
messenger nitric oxide (NO). Pharmacological selective inhibition of neuronal
NOS (nNOS) has the potential to be therapeutically beneficial in various
neurodegenerative diseases. Here, we present a structure-guided, selective nNOS
inhibitor design based on the crystal structure of lead compound 1 in nNOS. The
best inhibitor, 7, exhibited low nanomolar inhibitory potency and good isoform
selectivities (nNOS over eNOS and iNOS are 472-fold and 239-fold, respectively).
Consistent with the good selectivity, 7 binds to nNOS and eNOS with different
binding modes. The distinctly different binding modes of 7, driven by the
critical residue Asp597 in nNOS, offers compelling insight to explain its
isozyme selectivity, which should guide future drug design programs.
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