Abstract
Development of potent and isoform selective nitric oxide synthase (NOS) inhibitors is challenging because of the structural similarity in the heme active sites. One amino acid difference between NOS isoforms, Asp597 in rat neuronal NOS (nNOS) versus Asn368 in bovine endothelial NOS (eNOS), has been identified as the structural basis for why some dipeptide amide inhibitors bind more tightly to nNOS than to eNOS. We now have found that the same amino acid variation is responsible for substantially different binding modes and affinity for a new class of aminopyridine-based inhibitors.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Aminopyridines / metabolism*
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Animals
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Aspartic Acid / chemistry
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Aspartic Acid / genetics
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Aspartic Acid / metabolism*
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Cattle
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Computational Biology
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Enzyme Inhibitors / metabolism*
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Isoenzymes
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Models, Molecular
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Mutation / genetics
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Nitric Oxide / metabolism
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Nitric Oxide Synthase Type I / chemistry
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Nitric Oxide Synthase Type I / genetics
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Nitric Oxide Synthase Type I / metabolism*
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Nitric Oxide Synthase Type III / chemistry
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Nitric Oxide Synthase Type III / genetics
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Nitric Oxide Synthase Type III / metabolism*
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Protein Binding
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Protein Conformation
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Rats
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Static Electricity
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X-Ray Diffraction
Substances
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Aminopyridines
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Enzyme Inhibitors
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Isoenzymes
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Aspartic Acid
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Nitric Oxide
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Nitric Oxide Synthase Type I
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Nitric Oxide Synthase Type III