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PDBsum entry 5vui
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Oxidoreductase/oxidoreductase inhibitor
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PDB id
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5vui
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PDB id:
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| Name: |
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Oxidoreductase/oxidoreductase inhibitor
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Title:
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Structure of rat neuronal nitric oxide synthase heme domain in complex with 7-(((3-fluorophenyl)amino)methyl)quinolin-2-amine dihydrochloride
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Structure:
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Nitric oxide synthase, brain. Chain: a, b. Fragment: unp residues 297-718. Synonym: neuronal nitric oxide synthase, bnos, constitutive nos, nc- nos, nos type i, neuronal nos, nnos, peptidyl-cysteine s-nitrosylase nos1. Engineered: yes
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Source:
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Rattus norvegicus. Rat. Organism_taxid: 10116. Organ: brain. Gene: nos1, bnos. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008.
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Resolution:
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2.06Å
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R-factor:
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0.210
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R-free:
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0.252
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Authors:
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H.Li,T.L.Poulos
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Key ref:
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A.V.Pensa
et al.
(2017).
Hydrophilic, Potent, and Selective 7-Substituted 2-Aminoquinolines as Improved Human Neuronal Nitric Oxide Synthase Inhibitors.
J Med Chem,
60,
7146-7165.
PubMed id:
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Date:
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19-May-17
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Release date:
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16-Aug-17
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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.
407 a.a.
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Key: |
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PfamA domain |
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Secondary structure |
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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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J Med Chem
60:7146-7165
(2017)
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PubMed id:
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Hydrophilic, Potent, and Selective 7-Substituted 2-Aminoquinolines as Improved Human Neuronal Nitric Oxide Synthase Inhibitors.
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A.V.Pensa,
M.A.Cinelli,
H.Li,
G.Chreifi,
P.Mukherjee,
L.J.Roman,
P.Martásek,
T.L.Poulos,
R.B.Silverman.
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ABSTRACT
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Neuronal nitric oxide synthase (nNOS) is a target for development of
antineurodegenerative agents. Most nNOS inhibitors mimic l-arginine and have
poor bioavailability. 2-Aminoquinolines showed promise as bioavailable nNOS
inhibitors but suffered from low human nNOS inhibition, low selectivity versus
human eNOS, and significant binding to other CNS targets. We aimed to improve
human nNOS potency and selectivity and reduce off-target binding by (a)
truncating the original scaffold or (b) introducing a hydrophilic group to
interrupt the lipophilic, promiscuous pharmacophore and promote interaction with
human nNOS-specific His342. We synthesized both truncated and polar
2-aminoquinoline derivatives and assayed them against recombinant NOS enzymes.
Although aniline and pyridine derivatives interact with His342, benzonitriles
conferred the best rat and human nNOS inhibition. Both introduction of a
hydrophobic substituent next to the cyano group and aminoquinoline methylation
considerably improved isoform selectivity. Most importantly, these modifications
preserved Caco-2 permeability and reduced off-target CNS binding.
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