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References listed in PDB file
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Key reference
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Title
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Crystal structures for HIV-1 reverse transcriptase in complexes with three pyridinone derivatives: a new class of non-Nucleoside inhibitors effective against a broad range of drug-Resistant strains.
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Authors
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D.M.Himmel,
K.Das,
A.D.Clark,
S.H.Hughes,
A.Benjahad,
S.Oumouch,
J.Guillemont,
S.Coupa,
A.Poncelet,
I.Csoka,
C.Meyer,
K.Andries,
C.H.Nguyen,
D.S.Grierson,
E.Arnold.
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Ref.
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J Med Chem, 2005,
48,
7582-7591.
[DOI no: ]
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PubMed id
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Abstract
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In the treatment of AIDS, the efficacy of all drugs, including non-nucleoside
inhibitors (NNRTIs) of HIV-1 reverse transcriptase (RT), has been limited by the
rapid appearance of drug-resistant viruses. Lys103Asn, Tyr181Cys, and Tyr188Leu
are some of the most common RT mutations that cause resistance to NNRTIs in the
clinic. We report X-ray crystal structures for RT complexed with three different
pyridinone derivatives, R157208, R165481, and R221239, at 2.95, 2.9, and 2.43 A
resolution, respectively. All three ligands exhibit nanomolar or subnanomolar
inhibitory activity against wild-type RT, but varying activities against
drug-resistant mutants. R165481 and R221239 differ from most NNRTIs in that
binding does not involve significant contacts with Tyr181. These compounds
strongly inhibit wild-type HIV-1 RT and drug-resistant variants, including
Tyr181Cys and Lys103Asn RT. These properties result in part from an iodine atom
on the pyridinone ring of both inhibitors that interacts with the main-chain
carbonyl oxygen of Tyr188. An acrylonitrile substituent on R165481 substantially
improves the activity of the compound against wild-type RT (and several mutants)
and provides a way to generate novel inhibitors that could interact with
conserved elements of HIV-1 RT at the polymerase catalytic site. In R221239,
there is a flexible linker to a furan ring that permits interactions with
Val106, Phe227, and Pro236. These contacts appear to enhance the inhibitory
activity of R221239 against the HIV-1 strains that carry the Val106Ala,
Tyr188Leu, and Phe227Cys mutations.
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Secondary reference #1
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Title
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4-Benzyl and 4-Benzoyl-3-Dimethylaminopyridin-2(1h)-Ones: in vitro evaluation of new c-3-Amino-Substituted and c-5,6-Alkyl-Substituted analogues against clinically important HIV mutant strains.
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Authors
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A.Benjahad,
M.Croisy,
C.Monneret,
E.Bisagni,
D.Mabire,
S.Coupa,
A.Poncelet,
I.Csoka,
J.Guillemont,
C.Meyer,
K.Andries,
R.Pauwels,
M.P.De béthune,
D.M.Himmel,
K.Das,
E.Arnold,
C.H.Nguyen,
D.S.Grierson.
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Ref.
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J Med Chem, 2005,
48,
1948-1964.
[DOI no: ]
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PubMed id
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Secondary reference #2
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Title
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Roles of conformational and positional adaptability in structure-Based design of tmc125-R165335 (etravirine) and related non-Nucleoside reverse transcriptase inhibitors that are highly potent and effective against wild-Type and drug-Resistant HIV-1 variants.
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Authors
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K.Das,
A.D.Clark,
P.J.Lewi,
J.Heeres,
M.R.De jonge,
L.M.Koymans,
H.M.Vinkers,
F.Daeyaert,
D.W.Ludovici,
M.J.Kukla,
B.De corte,
R.W.Kavash,
C.Y.Ho,
H.Ye,
M.A.Lichtenstein,
K.Andries,
R.Pauwels,
M.P.De béthune,
P.L.Boyer,
P.Clark,
S.H.Hughes,
P.A.Janssen,
E.Arnold.
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Ref.
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J Med Chem, 2004,
47,
2550-2560.
[DOI no: ]
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PubMed id
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Secondary reference #3
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Title
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Crystal structures of 8-Cl and 9-Cl tibo complexed with wild-Type HIV-1 rt and 8-Cl tibo complexed with the tyr181cys HIV-1 rt drug-Resistant mutant.
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Authors
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K.Das,
J.Ding,
Y.Hsiou,
A.D.Clark,
H.Moereels,
L.Koymans,
K.Andries,
R.Pauwels,
P.A.Janssen,
P.L.Boyer,
P.Clark,
R.H.Smith,
M.B.Kroeger smith,
C.J.Michejda,
S.H.Hughes,
E.Arnold.
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Ref.
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J Mol Biol, 1996,
264,
1085-1100.
[DOI no: ]
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PubMed id
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Figure 1.
Figure 1. Chemical structures
with the numbering scheme used
and distances (E3.6 Å ) between
atoms of the TIBO inhibitor and of
the amino acid residues of the
NNIBP for: (a) 8-Cl TIBO (R86183,
tivirapine) complexed with wild-
type HIV-1 RT; (b) 8-Cl TIBO
complexed with Tyr181Cys mutant
HIV-1 RT; and (c) 9-Cl TIBO
(R82913) complexed with wild-type
HIV-1 RT. An NNIBP residue is
shown only if atoms of that residue
are E3.6 Å from an inhibitor atom
with the exception of Cys181 in (b).
The wings I and II portions of the
inhibitors in the butterfly-like anal-
ogy for NNRTIs (Ding et al., 1995a)
are indicated here and in sub-
sequent Figures by Roman nu-
merals I and II. The dotted line in (a)
indicates the subdivision of atoms
between wings I and II.
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Figure 5.
Figure 5. A stereoview of the superposition (based on the C
a
atoms of the b6-b10-b9 sheet) of the HIV-1 RT/DNA/Fab
complex structure (in gray) (Jacobo-Molina et al., 1993) on the HIV-1 RT/9-Cl TIBO complex structure (in cyan) in the
regions near the NNIBP and the polymerase active site showing the disposition of the b12-b13-b14 sheet containing
the primer grip. Bound 9-Cl TIBO in the HIV-1 RT/9-Cl TIBO complex is shown in gold and the two 3'-terminal
nucleotides 17 and 18 of the primer strand in the HIV-1 RT/DNA/Fab complex are shown with a yellow ball-and-stick
model. The broken line represents interactions between the primer grip and the primer terminal phosphate in the HIV-1
RT/DNA/Fab complex and the arrow indicates the movement of the primer grip that accompanies NNRTI binding.
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The above figures are
reproduced from the cited reference
with permission from Elsevier
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Secondary reference #4
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Title
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Structure and functional implications of the polymerase active site region in a complex of HIV-1 rt with a double-Stranded DNA template-Primer and an antibody FAB fragment at 2.8 a resolution.
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Authors
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J.Ding,
K.Das,
Y.Hsiou,
S.G.Sarafianos,
A.D.Clark,
A.Jacobo-Molina,
C.Tantillo,
S.H.Hughes,
E.Arnold.
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Ref.
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J Mol Biol, 1998,
284,
1095-1111.
[DOI no: ]
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PubMed id
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Figure 1.
Figure 1. Ribbon [Carson 1987] diagram showing the overall
structure of the HIV-1 RT/dsDNA/Fab28 complex. The subdomains of
the p66 and p51 subunits of HIV-1 RT are colored as follows:
fingers, blue; palm, red; thumb, green; connection, yellow; and
RNase H, orange. The bound dsDNA is shown with the template
strand as a dark gray ribbon and the primer strand as a light
gray ribbon; base-pairs are represented by bars. The monoclonal
antibody fragment Fab28 is shown with the light chain in light
gray and the heavy chain in dark gray.
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Figure 3.
Figure 3. (a) Structure of the polymerase active site region
of HIV-1 RT including the primer grip. Secondary structural
elements of the p66 palm subdomain are shown as red ribbons. The
three catalytically essential aspartic acid residues (Asp110,
Asp185, and Asp186) are shown with cyan side-chains. Tyr183 and
Met184, which form part of the conserved YMDD motif, are shown
with gold side-chains. Amino acid residues at the primer grip
are shown in green. The dsDNA is shown with the template strand
in dark gray and the primer strand in light gray. (b) A
schematic diagram showing interactions between the 3′-terminal
nucleotide of the primer strand (Pri1) and amino acid residues
at the polymerase active site, with selected distances given in
Å. Hydrogen-bonding interactions between the side-chain
O^δ1 atom of Asp185 and the 3′-OH of Pri1, and between the
amide nitrogen atom of Met230 of the primer grip and the
phosphate oxygen atom of Pri1 are indicated by heavy lines.
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The above figures are
reproduced from the cited reference
with permission from Elsevier
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Secondary reference #5
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Title
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Structure of HIV-1 rt/tibo r 86183 complex reveals similarity in the binding of diverse nonnucleoside inhibitors.
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Authors
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J.Ding,
K.Das,
H.Moereels,
L.Koymans,
K.Andries,
P.A.Janssen,
S.H.Hughes,
E.Arnold.
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Ref.
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Nat Struct Biol, 1995,
2,
407-415.
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PubMed id
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