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PDBsum entry 5adc
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Oxidoreductase
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PDB id
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5adc
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PDB id:
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| Name: |
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Oxidoreductase
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Title:
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Structure of rat neuronal nitric oxide synthase heme domain in complex with 7-(((5-((methylamino)methyl)pyridin-3-yl)oxy)methyl) quinolin-2- amine
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Structure:
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Nitric oxide synthase, brain. Chain: a, b. Fragment: heme domain, residues 297-718. Synonym: 1neuronal nitric oxide synthase, bnos, constitutive nos, nc- neuronal nos, n-nos, nnos, peptidyl-cysteine s-nitrosylase nos1. Engineered: yes
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Source:
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Rattus norvegicus. Norway rat. Organism_taxid: 10116. Expressed in: escherichia coli. Expression_system_taxid: 469008.
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Resolution:
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2.10Å
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R-factor:
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0.202
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R-free:
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0.253
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Authors:
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H.Li,T.L.Poulos
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Key ref:
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M.A.Cinelli
et al.
(2015).
Phenyl Ether- and Aniline-Containing 2-Aminoquinolines as Potent and Selective Inhibitors of Neuronal Nitric Oxide Synthase.
J Med Chem,
58,
8694-8712.
PubMed id:
DOI:
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Date:
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20-Aug-15
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Release date:
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28-Oct-15
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PROCHECK
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Headers
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References
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P29476
(NOS1_RAT) -
Nitric oxide synthase 1 from Rattus norvegicus
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Seq:
Struc:
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1429 a.a.
408 a.a.
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Key: |
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PfamA domain |
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Secondary structure |
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CATH domain |
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Enzyme class:
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E.C.1.14.13.39
- nitric-oxide synthase (NADPH).
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Reaction:
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2 L-arginine + 3 NADPH + 4 O2 + H+ = 2 L-citrulline + 2 nitric oxide + 3 NADP+ + 4 H2O
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2
×
L-arginine
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+
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3
×
NADPH
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+
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4
×
O2
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+
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H(+)
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=
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2
×
L-citrulline
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+
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2
×
nitric oxide
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+
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3
×
NADP(+)
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+
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4
×
H2O
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Molecule diagrams generated from .mol files obtained from the
KEGG ftp site
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DOI no:
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J Med Chem
58:8694-8712
(2015)
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PubMed id:
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Phenyl Ether- and Aniline-Containing 2-Aminoquinolines as Potent and Selective Inhibitors of Neuronal Nitric Oxide Synthase.
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M.A.Cinelli,
H.Li,
A.V.Pensa,
S.Kang,
L.J.Roman,
P.Martásek,
T.L.Poulos,
R.B.Silverman.
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ABSTRACT
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Excess nitric oxide (NO) produced by neuronal nitric oxide synthase (nNOS) is
implicated in neurodegenerative disorders. As a result, inhibition of nNOS and
reduction of NO levels is desirable therapeutically, but many nNOS inhibitors
are poorly bioavailable. Promising members of our previously reported
2-aminoquinoline class of nNOS inhibitors, although orally bioavailable and
brain-penetrant, suffer from unfavorable off-target binding to other CNS
receptors, and they resemble known promiscuous binders. Rearranged phenyl ether-
and aniline-linked 2-aminoquinoline derivatives were therefore designed to (a)
disrupt the promiscuous binding pharmacophore and diminish off-target
interactions and (b) preserve potency, isoform selectivity, and cell
permeability. A series of these compounds was synthesized and tested against
purified nNOS, endothelial NOS (eNOS), and inducible NOS (iNOS) enzymes. One
compound, 20, displayed high potency, selectivity, and good human nNOS
inhibition, and retained some permeability in a Caco-2 assay. Most promisingly,
CNS receptor counterscreening revealed that this rearranged scaffold
significantly reduces off-target binding.
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