 |
PDBsum entry 4d3b
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Oxidoreductase
|
PDB id
|
|
|
|
4d3b
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
PDB id:
|
|
|
|
| Name: |
|
Oxidoreductase
|
|
|
Title:
|
|
Structure of rat neuronal nitric oxide synthase heme domain in complex with n1-(2-(1h-imidazol-1-yl)pyrimidin-4-yl)-n2-(3- fluorophenethyl) ethane-1,2-diamine
|
|
Structure:
|
|
Nitric oxide synthase, brain. Chain: a, b. Fragment: heme domain, unp residues 297-718. Synonym: bnos, constitutive nos, nc-nos, nos type i, neuronal nos, n- nos, nnos, peptidyl-cysteine s-nitrosylase nos1, neuronal nitric oxide synthase. Engineered: yes
|
|
Source:
|
|
Rattus norvegicus. Norway rat. Organism_taxid: 10116. Expressed in: escherichia coli. Expression_system_taxid: 469008.
|
|
Resolution:
|
|
|
1.80Å
|
R-factor:
|
0.188
|
R-free:
|
0.226
|
|
|
Authors:
|
|
H.Li,T.L.Poulos
|
|
Key ref:
|
|
P.Mukherjee
et al.
(2015).
Novel 2,4-disubstituted pyrimidines as potent, selective, and cell-permeable inhibitors of neuronal nitric oxide synthase.
J Med Chem,
58,
1067-1088.
PubMed id:
DOI:
|
|
|
Date:
|
|
|
20-Oct-14
|
Release date:
|
24-Dec-14
|
|
|
|
|
|
|
PROCHECK
|
|
|
|
|
|
Headers
|
|
|
|
References
|
|
|
|
|
|
|
|
P29476
(NOS1_RAT) -
Nitric oxide synthase 1 from Rattus norvegicus
|
|
|
|
Seq:
Struc:
|
|
|
|
1429 a.a.
408 a.a.
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Key: |
 |
PfamA domain |
|
|
 |
Secondary structure |
|
 |
CATH domain |
|
|
|
|
|
|
|
|
|
|
|
|
|
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
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
|
|
|
|
|
|
| |
|
|
| |
|
DOI no:
|
J Med Chem
58:1067-1088
(2015)
|
|
PubMed id:
|
|
|
|
|
|
| |
|
Novel 2,4-disubstituted pyrimidines as potent, selective, and cell-permeable inhibitors of neuronal nitric oxide synthase.
|
|
P.Mukherjee,
H.Li,
I.Sevrioukova,
G.Chreifi,
P.Martásek,
L.J.Roman,
T.L.Poulos,
R.B.Silverman.
|
|
|
|
|
| |
ABSTRACT
|
|
|
|
| |
|
|
Selective inhibition of neuronal nitric oxide synthase (nNOS) is an important
therapeutic approach to target neurodegenerative disorders. However, the
majority of the nNOS inhibitors developed are arginine mimetics and, therefore,
suffer from poor bioavailability. We designed a novel strategy to combine a more
pharmacokinetically favorable 2-imidazolylpyrimidine head with promising
structural components from previous inhibitors. In conjunction with extensive
structure-activity studies, several highly potent and selective inhibitors of
nNOS were discovered. X-ray crystallographic analysis reveals that these type II
inhibitors utilize the same hydrophobic pocket to gain strong inhibitory potency
(13), as well as high isoform selectivity. Interestingly, select compounds from
this series (9) showed good permeability and low efflux in a Caco-2 assay,
suggesting potential oral bioavailability, and exhibited minimal off-target
binding to 50 central nervous system receptors. Furthermore, even with
heme-coordinating groups in the molecule, modifying other pharmacophoric
fragments minimized undesirable inhibition of cytochrome P450s from human liver
microsomes.
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
 |
 |
|
Links
