Scaffold rearrangement of dihydroxypyrimidine inhibitors of HIV integrase: Docking model revisited

Article abstract of DOI:10.1016/j.bmcl.2010.04.048

A series of dihydroxypyrimidine (DHP) derivatives were designed as inhibitors of HIV integrase (IN) based on known homology models. Through chemical synthesis and biochemical assays it was found that the activity profile of these compounds largely deviate

Full text of DOI:10.1016/j.bmcl.2010.04.048

Bioorganic & Medicinal Chemistry Letters 20 (2010) 3275–3279
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Scaffold rearrangement of dihydroxypyrimidine inhibitors of HIV
integrase: Docking model revisited
a,
Jing Tang a, Kasthuraiah Maddali b, Yves Pommier b, Yuk Y. Sham a, , Zhengqiang Wang
*
*
a Center for Drug Design, Academic Health Center, University of Minnesota, 516 Delaware St SE, Minneapolis, MN 55455, United States
b Laboratory of Molecular Pharmacology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of dihydroxypyrimidine (DHP) derivatives were designed as inhibitors of HIV integrase (IN)
based on known homology models. Through chemical synthesis and biochemical assays it was found that
the activity profile of these compounds largely deviates from predictions with existing models. With the
recently disclosed IN crystal structure of prototype foamy virus (PFV), a new HIV IN homology model was
constructed featuring a critical IN/DNA interface previously lacking. With this new model, docking results
completely corroborated observed biological activities. This new model should provide a more accurate
and improved platform for the design of new inhibitors of HIV IN.
Received 30 March 2010
Revised 9 April 2010
Accepted 12 April 2010
Available online 21 April 2010
Keywords:
HIV
Integrase
Ó 2010 Elsevier Ltd. All rights reserved.
Inhibitor design
Docking model
Binding mechanism
Integration of viral DNA into host genome is a defining step dur-
ing the replication of human immunodeficiency virus (HIV). This
process is catalyzed by a virally encoded enzyme integrase (IN)
involving two distinct enzymatic activities: a sequence-specific
endonuclease activity for 30 processing (30-P) and a non-specific
polynucleotidyltransferase for strand transfer (ST).1,2 Integration
allows HIV to establish stable viral latency3,4 which creates a diffi-
cult hurdle to complete viral eradication and profoundly impacts
the chemotherapy of infected hosts. Stalling this process offers
an appealing venue for the design and development of anti-HIV
drugs. Due to the lack of cellular counterpart, IN represents a par-
ticularly attractive target for the design of novel antivirals. Efforts
in this line have led to the discovery of a few major inhibitor chem-
otypes5 represented by quinolone compound 1 (elvitegravir)6,7 and
dihydroxypyrimidine (DHP) compound 2 (raltegravir)8,9 (Fig. 1),
with the latter being the only FDA approved IN inhibitor.
despite tremendous efforts in elucidating IN structure13–19 crystal-
lization of DNA bound HIV IN has proved to be a daunting chal-
lenge due to substantial technical barriers. As a result detailed
mechanism of IN catalysis remains elusive, which greatly hinders
structure-based design for improved inhibitors. To facilitate new
inhibitor design various pharmacophore models have been
developed.20–29 These models entail two common structural com-
ponents for IN binding: a diketoacid (DKA) or its bioisosteric
chelating triad capable of binding two Mg2+ ions, and a spatially
properly aligned hydrophobic benzyl moiety. Based on these mod-
els, scaffold rearrangement involving repositioning the terminal
benzyl moiety from one end to the other could yield new inhibitors
with retained binding ability. This operation is exemplified in
Figure 2. Naphthyridine compound 3 (L-870,810, Merck)30 and
naphthyridinone compound 4 (GSK)31,32 represent two major IN
inhibitor chemotypes, both exhibiting exceptional inhibitory activ-
ity against ST. A quick structural examination reveals that these
two share an identical two-metal chelating functionality (high-
lighted in red) constructed on a very similar bicyclic ring system,
whereas the terminal benzyl groups (marked in blue) are posi-
tioned at the opposite end of the scaffold (Fig. 2).
Notably most IN inhibitors under development selectively inhi-
bit ST.10,11 Catalysis of ST most likely involves a well-coordinated
high-order architecture consisting of IN, viral and host DNA sub-
strates as well as certain cellular factors.12 Inhibitors are believed
to be binding to and stabilizing DNA/IN interface.2 Nevertheless,
This observation prompted us to explore the possibility of
generating new chemotypes from the DHP scaffold, the most suc-
cessful molecular backbone for IN inhibitors as manifested by ral-
tegravir (2, Fig. 1). In this event, we designed two types of new
inhibitors from a model DHP inhibitor 533: compound 6 where
the benzyl group is transposed from the amide end to N-3 site,
Abbreviations: HIV, human immunodeficiency virus; IN, integrase; 30-P, 30
processing; ST, strand transfer; DHP, dihydroxypyrimidine; DKA, diketoacid; PDB,
protein data bank; PFV, prototype foamy virus; CCD, catalytic core domain.
* Corresponding authors. Tel.: +1 (612) 625 8255; fax: +1 (612) 625 8154 (Y.Y.S.);
tel.: +1 (612) 626 7025; fax: +1 (612) 625 8154 (Z.W.).
E-mail addresses: shamx002@umn.edu (Y.Y.Sham),wangx472@umn.edu (Z. Wang).
0960-894X/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2010.04.048

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J. Tang et al. / Bioorg. Med. Chem. Lett. 20 (2010) 3275–3279
F
O
N
O
F
O
N
Cl
OH
OH
N
N
N
H
N
H
N
O
O
O
O
OH
2,
1, Elvitegravir
Raltegravir
Figure 1. Representative IN ST inhibitors.
O
O
S
N
N
N
O
O
F
H
N
H
N
F
N
OMe
N
OH
Benzyl repositioning
OH
O
3, L-870,810
4
ST IC50 = 5.0 nMa
ST IC50 = 4.0 nMa
F
F
N
N
HN
N
HN
N
H
N
H
N
H
N
?
?
F
O
O
O
OH
O
OH
O
OH
O
5
6
7
ST IC50 = 60 nMb
Figure 2. Scaffold rearrangement of known ST inhibitors. Potent inhibitors 3 and 4 reflect a benzyl group repositioning on a common naphthyridine scaffold. The same
operation within DHP inhibitor scaffold 5 could generate two new type of IN inhibitors 6 and 7. Ref: a31 and b.33
Figure 3. Docking of compounds 5–7 into previously reported homology models of HIV IN. Both models of Chen et al. (a)34 and Chimirri et al. (PDB: 1WKN) (b)35 allowed
reasonable mode of binding of compounds 5 and 6 in which the parafluorobenzyl substituent binds into each of their proposed hydrophobic binding pocket.

J. Tang et al. / Bioorg. Med. Chem. Lett. 20 (2010) 3275–3279
3277
and compound 7 where the benzyl group is repositioned to the C-2
site.
Compound 6 was prepared in a similar manner from compound
15 via intermediate 16 (Scheme 2).
To validate this design, we performed molecular docking using
two known homologous docking models34,35 constructed based on
Tn5 transposes. In these models, the ligands were placed manually
into the potential binding site and the final models were validated
via direct correlation with site direct mutagenesis studies.34,35
Docking study was carried out by overlaying each of the com-
pounds onto the bound ligand within the already validated binding
site of the reported modeled complex followed by restraint energy
minimization using OPLS 2005 forcefield36 with generalized born
solvent accessible (GB/SA) implicit solvent model.37 In line with
the common pharmacophore model, these docking models suggest
that the chelating triad of the inhibitor interacts with Mg2+ ions in
a relatively hydrophilic region, anchoring the inhibitor onto the
protein surface, whereas the benzyl moiety fits in a highly hydro-
phobic cavity near the active site. Direct interaction is not observed
between inhibitor and viral DNA. As shown in Figure 3, compounds
5 and 6 are perfectly docked into both homologous models. The
docking of compound 7 is slightly off in model (a) though the ter-
minal benzyl still makes contact with the hydrophobic cavity,
whereas in model (b) compound 7 seems to fit well in this cavity.
Overall, these docking results support scaffold rearrangements de-
scribed in Figure 2.
Chemical synthesis of these compounds was achieved based on
reported strategy (Scheme 1).31,33 The key DHP carboxylate inter-
mediate 13 was prepared from commercially available nitrile 12
in three steps. Direct amidation of ester 13 under microwave
condition provides an efficient access to compounds 7–9. The
saponification of intermediate 13 also led to the preparation of
DHP carboxylic acid 10. The preparation of N-3 alkylated analogues
was effected through a 5-OH protected intermediate. In this event,
13 was benzoylated to give intermediate 14, which was methyl-
ated with methyl iodide followed by a microwave-assisted amida-
tion to produce compound 11.
All final compounds were evaluated for their ability to inhibit
the two distinct steps of integration: 30-P and ST. The assay results
are summarized in Table 1. In our assay compound 5 shows selec-
tive inhibitory activity against ST at low micromolar concentration,
whereas all other compounds exhibit a 40 to 100-fold higher IC50
value against ST. Although a general trend of selective inhibition
against ST can still be observed with compounds 6–11 (Table 1),
their strikingly low inhibitory activity against ST when compared
to compound 5 is extremely intriguing given that these compounds
Table 1
Assay results of compounds 6–11 against HIV IN
O
R1
R2
OH
R3
N
N
O
Compds R1
R2
R3
30-P IC50
(lM) ST IC50 (lM)
5a
6
H
Me
Me
NHBn-4-F
NHMe
111 18
>333
2.6 0.1
111
4-F-
Bn
H
7
4-F-
Bn
4-F-
Bn
4-F-
Bn
4-F-
Bn
NHMe
>333
>333
169
206
>333
243
241
8
H
NH(CH2)2OMe
9
H
NH(CH2)3NMe2 >333
10
11
H
OH
>333
>333
Me
4-F-
Bn
NHMe
a
Reported ST IC50 was 0.06
l
M.33
O
N
O
F
F
OH
OMe
F
OH
NHR
HN
13
a-c
HN
d
N
RNH2
N
12
O
O
7
: R = Me
8: R = CH2CH2OMe
9: R = CH2CH2CH2NMe2
h
e
O
N
F
R
OBz
O
O
O
N
N
F
OH
F
OH
OH
OMe
N
HN
g
NHMe
14: R = H
17: R = Me
N
11
f
O
10
O
Scheme 1. Synthesis of compounds 7–11. Reagents and conditions: (a) NH2OH, MeOH, 60 °C, 7 h, 65%; (b) dimethylacetylenedicarboxlate, MeOH, rt, quantitative yield; (c)
xylene, MW, 140 °C, 40 min, 23%; (d) RNH2, MW, 150 °C, 4 min, 50–76%; (e) benzoyl chloride, pyridine, 66%; (f) MeI, Cs2CO3, THF, 40 °C, 57%; (g) MeNH2 (33% solution in
EtOH), MW, 150 °C, 4 min, 55%; (h) NaOH, MeOH, rt, overnight, 27%.
O
O
N
O
OH
NHMe
R
OBz
OMe
OH
OMe
N
N
HN
a
c
F
N
N
O
O
O
16: R = H
b
15
6
18: R = 4-F-Benzyl
Scheme 2. Synthesis of compound 6. Reagents and conditions: (a) benzoyl chloride, pyridine, 89%; (b) 4-F-benzyl bromide, Cs2CO3, THF, 80 °C, 30%; (c) MeNH2, MW, 150 °C,
4 min, 50%.

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J. Tang et al. / Bioorg. Med. Chem. Lett. 20 (2010) 3275–3279
appear to be binding to IN according to both homologous docking
models. Apparently to gain better understanding on HIV IN binding
it is imperative to introduce a new docking model significantly dif-
ferent from the existing ones.
eling was carried out using the Schrödinger modeling suite pack-
age.39 The models of the HIV catalytic core domain (CCD)/viral
DNA complex were homology modeled using Prime v3.1 in silico
by replacing the viral DNA and IN enzyme sequences of PFV with
those of HIV (GenBank: AAC37875.1). Since the catalytic core do-
main of the HIV-1 IN was previously solved,13,19 the sequence
alignment used for the homology modeling was based on the sec-
ondary structure alignment of the PFV and HIV-1 IN CCD to identify
the structure conserve regions (Fig. S1A). The backbone RMSD be-
tween the two CCD’s was 1.13 Å showing a highly conserved pro-
tein fold. All side chains were optimized by standard side chain
The recent publication38 of the first crystal structures of DNA-
bound retroviral IN allowed us to construct new docking models
for HIV IN. As these structures suggested an induced fit mechanism
of inhibition by the displacement of 30adenosine, two models were
constructed based on the original X-ray crystal structures of IN
from prototype foamy virus (PFV) (PDB: 3L2T and 3L2U),38
a
retro-lentivirus belonging to the same viral genus as HIV. All mod-
Figure 4. A new HIV IN model docked based on 3L2T with raltegravir (a) and 3L2U with elvitegravir (b). The observed modes of binding were consistent with that of PFV IN X-
ray structures.36
Figure 5. Docking of compounds 1–7 into the new homology model of HIV IN (a–f). Overlay of compounds 1 and 2 showed two distinct modes of binding to the Mg2+ ions
while retaining reasonable overlap of the halobenzyl group within the hydrophobic binding pocket (a). Major protein and viral DNA residues which formed the interfacial
DNA/protein hydrophobic pocket (A17, G4 and C16, P145) (in dotted circle) and the E152-D64-D116 motif which chelates to the two Mg2+ ions within the binding pocket are
highlighted (d).

J. Tang et al. / Bioorg. Med. Chem. Lett. 20 (2010) 3275–3279
6. Shimura, K.; Kodama, E. Future HIV Ther. 2008, 2, 411.
3279
optimization protocol using PrimeX. The final models were further
refined by restraint energy minimization using OPLS 2005 force-
field36 with GB/SA implicit solvent model. Docking of all com-
pounds in the new homology model was carried out using Glide
v2.5 at Standard Precision40 with both Mg2+ ions and the interfacial
hydrophobic pocket between the HIV IN and DNA defined as re-
quired constraints. Validation of both models were carried out by
docking of either raltegravir (2, model a) or elvitegravir (1, model
b) into the ligand binding site and structure comparison with the
original X-ray structure of PFV IN (Fig. 4). Consistent with observa-
tions from the original crystallographic studies, in these models
inhibitors seem to adopt an orientation perpendicular to the pro-
tein surface with the chelating group binding to both Mg2+ ions.
This chelation then allows the terminal benzyl group to induce a
pocket by taking the space originally occupied by the terminal
adenosine on the 30 end of viral DNA. Overall, the binding of IN
inhibitors conforms to a previously proposed interfacial inhibition
mechanism2 as they bind all three key elements: the enzyme by
hydrophobic and Van der Waals interactions; the metals by chela-
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tion; and the DNA by p–p stacking. Further docking of compounds
1–7 was conducted with the model based on PDB: 3L2T (model a).
Remarkably all active compounds 1–5 are docked similarly with
the terminal benzyl group optimally oriented to fill in the newly
created pocket (Fig. 5a–d). As a result, close contacts are observed
between this terminal benzyl group and both viral DNA and neigh-
boring IN amino acids residues (Fig. 5 d). By contrast, the terminal
benzyl group of compound 6 is skewed away from the pocket
(Fig. 5 e) and compound 7 adopts a conformation in which the ben-
zyl group is pointing to the opposite direction of the pocket (Fig. 5
f). These docking results are in agreement with observed inhibitory
activities against HIV IN and prove that this new docking model is
robust.
In conclusion, we have designed and synthesized a series of new
DHP type IN inhibitors based on known pharmacophore and
homologous docking models. The unexpected assay results led us
to construct a new docking model for HIV IN binding, which pro-
vides docking results that strongly corroborate observed biological
activities. We expect this model to serve as a useful platform for
the design and discovery of novel HIV IN inhibitors.
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Acknowledgments
This research was supported by the Center for Drug Design at
the University of Minnesota and by the Center for Cancer Research,
National Cancer Institute, NIH. We thank Professor Robert Vince for
discussion and the University of Minnesota Supercomputing Insti-
tute for providing computational resources.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bmcl.2010.04.048.
36. Jorgensen, W. L.; Maxwell, D. S.; Tirado-Rives, J. J. Am. Chem. Soc. 1996, 118,
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