 |
PDBsum entry 5uo2
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Oxidoreductase/oxidoreductase inhibitor
|
PDB id
|
|
|
|
5uo2
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
PDB id:
|
|
|
|
| Name: |
|
Oxidoreductase/oxidoreductase inhibitor
|
|
|
Title:
|
|
Structure of human neuronal nitric oxide synthase heme domain in complex with 7-[(3-ethyl-5-((methylamino)methyl)phenoxy) methyl]quinolin-2-amine
|
|
Structure:
|
|
Nitric oxide synthase, brain. Chain: a, b. Fragment: unp residues 302-722. Synonym: constitutive nos,nc-nos,nos type i,neuronal nos,nnos, peptidyl-cysteine s-nitrosylase nos1,bnos. Engineered: yes. Mutation: yes. Other_details: residues 345 to 349 are disordered.
|
|
Source:
|
|
Homo sapiens. Human. Organism_taxid: 9606. Organ: brain. Gene: nos1. Expressed in: escherichia coli. Expression_system_taxid: 469008.
|
|
Resolution:
|
|
|
1.95Å
|
R-factor:
|
0.185
|
R-free:
|
0.235
|
|
|
Authors:
|
|
H.Li,T.L.Poulos
|
|
Key ref:
|
|
M.A.Cinelli
et al.
(2017).
Nitrile in the Hole: Discovery of a Small Auxiliary Pocket in Neuronal Nitric Oxide Synthase Leading to the Development of Potent and Selective 2-Aminoquinoline Inhibitors.
J Med Chem,
60,
3958-3978.
PubMed id:
|
|
|
Date:
|
|
|
31-Jan-17
|
Release date:
|
03-May-17
|
|
|
|
|
|
|
PROCHECK
|
|
|
|
|
|
Headers
|
|
|
|
References
|
|
|
|
|
|
|
|
P29475
(NOS1_HUMAN) -
Nitric oxide synthase 1 from Homo sapiens
|
|
|
|
Seq:
Struc:
|
|
|
|
1434 a.a.
416 a.a.*
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Key: |
|
 |
Secondary structure |
|
|
*
PDB and UniProt seqs differ
at 2 residue positions (black
crosses)
|
|
|
|
|
|
|
|
|
|
|
|
|
Enzyme class:
|
|
E.C.1.14.13.39
- nitric-oxide synthase (NADPH).
|
|
|
|
|
|
|
Reaction:
|
|
2 L-arginine + 3 NADPH + 4 O2 + H+ = 2 L-citrulline + 2 nitric oxide + 3 NADP+ + 4 H2O
|
|
|
|
|
|
2
×
L-arginine
|
+
|
3
×
NADPH
|
+
|
4
×
O2
|
+
|
H(+)
|
=
|
2
×
L-citrulline
|
+
|
2
×
nitric oxide
|
+
|
3
×
NADP(+)
|
+
|
4
×
H2O
|
|
|
|
|
|
|
|
|
|
|
|
|
Molecule diagrams generated from .mol files obtained from the
KEGG ftp site
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
|
|
|
|
|
|
| |
|
|
| |
|
|
J Med Chem
60:3958-3978
(2017)
|
|
PubMed id:
|
|
|
|
|
|
| |
|
Nitrile in the Hole: Discovery of a Small Auxiliary Pocket in Neuronal Nitric Oxide Synthase Leading to the Development of Potent and Selective 2-Aminoquinoline Inhibitors.
|
|
M.A.Cinelli,
H.Li,
G.Chreifi,
T.L.Poulos,
R.B.Silverman.
|
|
|
|
|
| |
ABSTRACT
|
|
|
|
| |
|
|
Neuronal nitric oxide synthase (nNOS) inhibition is a promising strategy to
treat neurodegenerative disorders, but the development of nNOS inhibitors is
often hindered by poor pharmacokinetics. We previously developed a class of
membrane-permeable 2-aminoquinoline inhibitors and later rearranged the scaffold
to decrease off-target binding. However, the resulting compounds had decreased
permeability, low human nNOS activity, and low selectivity versus human eNOS. In
this study, 5-substituted phenyl ether-linked aminoquinolines and derivatives
were synthesized and assayed against purified NOS isoforms. 5-Cyano compounds
are especially potent and selective rat and human nNOS inhibitors. Activity and
selectivity are mediated by the binding of the cyano group to a new auxiliary
pocket in nNOS. Potency was enhanced by methylation of the quinoline and by
introduction of simple chiral moieties, resulting in a combination of
hydrophobic and auxiliary pocket effects that yielded high (∼500-fold) n/e
selectivity. Importantly, the Caco-2 assay also revealed improved membrane
permeability over previous compounds.
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
 |
 |
|
Links
