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References listed in PDB file
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Key reference
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Title
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Design, Synthesis, And activity of 2-Imidazol-1-Ylpyrimidine derived inducible nitric oxide synthase dimerization inhibitors.
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Authors
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D.D.Davey,
M.Adler,
D.Arnaiz,
K.Eagen,
S.Erickson,
W.Guilford,
M.Kenrick,
M.M.Morrissey,
M.Ohlmeyer,
G.Pan,
V.M.Paradkar,
J.Parkinson,
M.Polokoff,
K.Saionz,
C.Santos,
B.Subramanyam,
R.Vergona,
R.G.Wei,
M.Whitlow,
B.Ye,
Z.S.Zhao,
J.J.Devlin,
G.Phillips.
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Ref.
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J Med Chem, 2007,
50,
1146-1157.
[DOI no: ]
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PubMed id
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Abstract
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By the screening of a combinatorial library for inhibitors of nitric oxide (NO)
formation by the inducible isoform of nitric oxide synthase (iNOS) using a
whole-cell assay, 2-(imidazol-1-yl)pyrimidines were identified. Compounds were
found to inhibit the dimerization of iNOS monomers, thus preventing the
formation of the dimeric, active form of the enzyme. Optimization led to the
selection of the potent, selective, and orally available iNOS dimerization
inhibitor, 21b, which significantly ameliorated adjuvant-induced arthritis in a
rat model. Analysis of the crystal structure of the 21b--iNOS monomer complex
provided a rationalization for both the SAR and the mechanism by which 21b
blocks the formation of the protein--protein interaction present in the dimeric
form of iNOS.
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Secondary reference #1
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Title
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The rational design of inhibitors of nitric oxide formation by inducible nitric oxide synthase.
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Authors
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M.Whitlow,
M.Adler,
D.Davey,
Q.Huang,
S.Koovakkat,
J.F.Parkinson,
E.Pham,
M.Polokoff,
W.Xu,
S.Yuan,
G.Phillips.
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Ref.
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Bioorg Med Chem Lett, 2007,
17,
2505-2508.
[DOI no: ]
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PubMed id
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Secondary reference #2
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Title
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3-[4-(1-Imidazolyl)phenoxy]-1-Piperonyl piperidine analogs as potent and selective inhibitors of nitric oxide formation
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Authors
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R.G.Wei,
M.Adler,
D.Davey,
E.Ho,
R.Mohan,
M.Polokoff,
J.L.Tseng,
M.Whitlow,
W.Xu,
S.Yuan,
G.Phillips.
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Ref.
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to be published ...
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Secondary reference #3
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Title
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Allosteric inhibitors of inducible nitric oxide synthase dimerization discovered via combinatorial chemistry.
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Authors
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K.Mcmillan,
M.Adler,
D.S.Auld,
J.J.Baldwin,
E.Blasko,
L.J.Browne,
D.Chelsky,
D.Davey,
R.E.Dolle,
K.A.Eagen,
S.Erickson,
R.I.Feldman,
C.B.Glaser,
C.Mallari,
M.M.Morrissey,
M.H.Ohlmeyer,
G.Pan,
J.F.Parkinson,
G.B.Phillips,
M.A.Polokoff,
N.H.Sigal,
R.Vergona,
M.Whitlow,
T.A.Young,
J.J.Devlin.
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Ref.
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Proc Natl Acad Sci U S A, 2000,
97,
1506-1511.
[DOI no: ]
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PubMed id
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Figure 1.
Fig. 1. (A) The synthetic steps used to prepare the
encoded combinatorial chemical library on a polymeric support.
(B) The distribution frequency of synthons in active compounds
from the combinatorial library. (C) Compound 1
(N-[(1,3-benzodioxol-5-yl)methyl]-1-[6-chloro-2-(1H-imidazol-1-yl)pyrimidin-4-yl]piperazine-2-acetamide)
is one of the compounds that was found by screening the library.
Compound 2 is
(N-[(1,3-benzodioxol-5-yl)methyl]-1-[2-(1H-imidazol-1-yl)pyrimidin-4-yl]-4-(methoxycarbonyl)-piperazine-2-acetamide.
Compound 3, tritiated on the propionamide moiety, is the analog
used in the competitive binding assay
(N-[(1,3-benzodioxol-5-yl)methyl]-4-(ethylcarbonyl)-1-[2-(1H-imidazol-1-yl)pyrimidin-4-yl]piperazine-2-acetamide).
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Figure 5.
Fig. 5. The 2.25-Å resolution crystal structure of
the 2-murine iNOS  114 complex
and comparison to the murine iNOS dimer structure. Two views of
the refined model of the 2-murine iNOS 114 complex
are shown. Compound 2 (green) and heme (dark red) both are shown
with blue nitrogens and red oxygens. The sulfur (yellow) of
Cys-194 (magenta) coordinates the heme iron (yellow sphere). The
water molecules described in the text are shown as red spheres,
and in Tyr-367, Tyr-485, and Gln-257 side chains are shown in
orange with red oxygens and blue nitrogens. Both iron
coordination and hydrogen bonds are shown as dashed lines; other
iNOS 114 atoms
are shown in gray. Numerous residues are not shown for clarity,
including residues 486-496 and the side chains of Val-346,
Asn-348, and Met-349 in A and Gln-257 and surrounding residues
(241-345) in B.
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Secondary reference #4
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Title
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The structure of nitric oxide synthase oxygenase domain and inhibitor complexes.
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Authors
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B.R.Crane,
A.S.Arvai,
R.Gachhui,
C.Wu,
D.K.Ghosh,
E.D.Getzoff,
D.J.Stuehr,
J.A.Tainer.
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Ref.
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Science, 1997,
278,
425-431.
[DOI no: ]
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PubMed id
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Figure 3.
Fig. 3. Mobility, surface properties, and shape. (A) C  trace of
NOS[ox]  114 (cubic
crystal form) colored by the crystallographic^ temperature
factor (low to high B factors colored blue to red) and displayed
with heme and mutation sites that affect function. Mutation
sites (side chains displayed and labeled by residue number)
affecting dimerization, L-Arg binding, or H[4]B binding
(defined^ in Fig. 2) cluster to highly mobile (red) projecting
regions. The view is rotated by about 45° from Fig. 1 about
a vertical axis. (B) Solvent-accessible molecular surface of
flattened^ (left) and concave (center) face. The orientation is
the same^ as in (A). The exposed heme edge (gold), residues
contributing to the distal pocket (cyan), and exposed conserved
hydrophobic^ residues (green) (defined in Fig. 2) map to the
same flattened^ face of the molecule and cluster in the regions
of high mobility and mutational sensitivity shown in (A), making
this surface the^ prime candidate for a symmetric dimer
interface. (C) Solvent-accessible^ molecular surface of the
narrow curved face. This face has few conserved exposed
hydrophobic residues. The view is rotated 90° from (A) and
(B) around a vertical axis.
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Figure 5.
Fig. 5. Comparison of the proximal heme-binding regions of
iNOS[ox] and cytochrome P450s. Structural elements contributing
to the proximal heme-binding regions of iNOS[ox] 114 and
P450[cam] (cyan C traces)
are substantially different. Only the proximal Cys ligands
(magenta bonds with yellow sulfur atoms, bound to gold^ hemes)
and immediately COOH-terminal three residues (magenta C traces)
have similar conformations. In iNOS[ox], Cys194 lies at the
COOH-terminal end of a helix and precedes an extended^ strand,
whereas in P450[cam], Cys357 lies at the NH[2]-terminal end of a
helix and follows an extended^ strand. Also, these two cysteine
thiolates bind opposite faces of iron protoporphyrin IX. C positions
for iNOS[ox] 114
residues 194 to 197 were superimposed with P450[cam] residues
357^ to 360 and then separated for clarity.
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The above figures are
reproduced from the cited reference
with permission from the AAAs
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Secondary reference #5
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Title
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Characterization of the inducible nitric oxide synthase oxygenase domain identifies a 49 amino acid segment required for subunit dimerization and tetrahydrobiopterin interaction.
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Authors
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D.K.Ghosh,
C.Wu,
E.Pitters,
M.Moloney,
E.R.Werner,
B.Mayer,
D.J.Stuehr.
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Ref.
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Biochemistry, 1997,
36,
10609-10619.
[DOI no: ]
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PubMed id
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