X-ray and molecular modelling in fragment-based design of three small quinoline scaffolds for HIV integrase inhibitors

Article abstract of DOI:10.1016/j.bmc.2011.01.045

Crystal structures of three small molecular scaffolds based on quinoline, 2-methylquinoline-5,8-dione, 5-hydroxy-quinaldine-6-carboxylic acid and 8-hydroxy-quinaldine-7-carboxylic acid, were characterised. 5-Hydroxy- quinaldine-6-carboxylic acid was co-crystallized with cobalt(II) chloride to form a model of divalent metal cation-ligand interactions for potential HIV integrase inhibitors. Molecular docking into active site of HIV IN was also performed on 1WKN PDB file. Selected ligand-protein interactions have been found specific for active compounds. Studied structures can be used as scaffolds in fragment-based design of new potent drugs.

Full text of DOI:10.1016/j.bmc.2011.01.045

Bioorganic & Medicinal Chemistry 19 (2011) 1606–1612
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
X-ray and molecular modelling in fragment-based design of three small
quinoline scaffolds for HIV integrase inhibitors
Katarzyna Majerz-Maniecka a, , Robert Musiol b, , Agnieszka Skórska-Stania a, Dominik Tabak b,
⇑
⇑
Pawel Mazur b, Barbara J. Oleksyn a, Jaroslaw Polanski b
a Faculty of Chemistry, Jagiellonian University, ul. R. Ingardena 3, 30-060 Kraków, Poland
b Institute of Chemistry, University of Silesia, ul. Szkolna 9, 40-007 Katowice, Poland
a r t i c l e i n f o
a b s t r a c t
Article history:
Crystal structures of three small molecular scaffolds based on quinoline, 2-methylquinoline-5,8-dione, 5-
hydroxy-quinaldine-6-carboxylic acid and 8-hydroxy-quinaldine-7-carboxylic acid, were characterised.
5-Hydroxy-quinaldine-6-carboxylic acid was co-crystallized with cobalt(II) chloride to form a model of
divalent metal cation–ligand interactions for potential HIV integrase inhibitors. Molecular docking into
active site of HIV IN was also performed on 1WKN PDB file. Selected ligand–protein interactions have
been found specific for active compounds. Studied structures can be used as scaffolds in fragment-based
design of new potent drugs.
Received 23 November 2010
Revised 20 January 2011
Accepted 21 January 2011
Available online 27 January 2011
Keywords:
HIV integrase
Quinolines
Ó 2011 Elsevier Ltd. All rights reserved.
Fragment-based drug design
Crystal structure
1. Introduction
knowledge of all interactions which occur in solutions or crystals of
molecules proposed as scaffolds is very important for better under-
Recently the fragment-based approach (F-BA) to drug discovery
has gained stronger attention than ever before. During the last
10 years this methodology has been intensively developing and
now it can be successfully used as an alternative for poorly effec-
tive HTS.1,2 However, it should be remembered that the molecules
used as fragments do not possess high activity, but they are much
more druggable than huge, sophisticated structures usually
pointed out in HTS. Thus, in F-BA we are looking rather for possi-
bility of creating a new drug than for activity. Successful molecular
scaffolds should be easily accessible and transferable into real
drug. Probably the best way to achieve this aim is to explore the
so-called privileged structures as a scaffold.3 Unfortunately there
are no simple rules that specify which structure is really privileged.
On the other hand quinoline and its derivatives such as quinolone
antibiotics can be the most spectacular examples of the potential
efficiency of this system.4 Quinine molecule, which also contains
a quinoline moiety, proves the Nature preference for this system.
Quinoline scaffold can also be found in many classes of other bio-
logically active compounds used as antifungals, antibacterials and
antiprotozoic drugs5–8 as well as antituberculotic agents.9 Some
quinoline analogues showed also antineoplastic activity. Thorough
standing its fate in biological systems and for (Q)SAR studies. Cer-
tain specific interactions are able to change crucial parameters of
molecules or even to change the structure via shift of tautomeric
equilibrium.10 Here we wish to report our findings concerning
intermolecular interactions in the crystal structures of three quin-
oline-based scaffolds that are promising in design of new antiviral
and anticancer agents (Fig. 1). In the next stage, we applied molec-
ular docking to correlate data derived from crystal structure and
biological activity.
Quinoline-5,8-dione is a substantial molecular fragment of lav-
endomycin and related compounds (Fig. 2). Lavendomycin was
originally isolated from the fermented broth of Streptomyces lav-
endulae and the compounds of this class were identified in the
1970’s as anti-tumour agents. Although the toxicity of lavendomy-
cin makes it unsuitable for clinical use, its activity has inspired sev-
eral investigations.11–14 This scaffold was found to be very
O
OH
OH
O
O
HO
NH
N
1
N
N
2
3
O
⇑
Corresponding authors.
E-mail addresses: majerz.maniecka@gmail.com (K. Majerz-Maniecka), robert.
OH
O
musiol@us.edu.pl (R. Musiol).
Figure 1. Three molecular scaffolds as fragments of HIV integrase inhibitors.
0968-0896/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2011.01.045

K. Majerz-Maniecka et al. / Bioorg. Med. Chem. 19 (2011) 1606–1612
1607
O
O
O
O
O
MeO
MeO
H
N
N
COOH
O
H2N
N
N
N
COOH
CH3
H2N
H2N
N
O
H2N
CH3
OH
H2N
CH3
OH
N
OMe
OMe
OMe
OMe
Lavendamycin
Streptonigrone
Streptonigrin
Figure 2. Quinolinone-based antibiotics show the importance of quinoline as molecular fragment.
promising in our recent investigation of anticancer agents with
activity against P-388 leukaemia cells twice as high as that of
cisplatin.15
Compound 1 was obtained from 2-methyl-8-hydroxyquinoline
through nitration, reduction and finally oxidation to give crude
product (purified by crystallization from EtOH) as yellow solid,
80% yield, mp 258 °C (lit. mp 260.5 °C29). Compound 2 was ob-
tained from 2-hydroxy-4-aminobenzoic acid and crotonaldehyde
in Skraup reaction.16 8-Hydroxy-2-methylquinoline-7-carboxylic
acid 3 was obtained in Kolbe–Schmidt reaction from 8-hydroxy-
quinaldine as described earlier.21
5-Hydroxy-quinaldine-6-carboxylic acid (Fig. 1(2)) proved its
applicability in design of novel HIV integrase inhibitors16,17 and her-
bicidal agents.18 Its isomer, 8-hydroxy-quinalidne-7-carboxylic
acid, is a well-known scaffold used in synthesis of potent HIV integr-
ase inhibitors (e.g., FZ41), antifungal and anticancer agents.19–22
Most of HIV integrase inhibitors are believed to interact with
divalent metal cations such as magnesium or manganese, located
at the protein active site.23 Recently retroviral intasome has been
elucidated by mean crystal structure of IN from PFV virus.24,25 This
can also confirmed importance of this mechanism. Elvitegravir and
raltegravir two known potent inhibitors of HIV integrase were
found engaging two Mg cations in the active site of the intasome.26
It seems obvious that knowledge of interactions between an inhib-
itor molecule and cations is crucial for better understanding its
mode of action and explaining its activity and/or selectivity.27 Fur-
thermore they can also be useful in elucidation the problem of
drug resistance caused by small mutations.28
2.2. Crystal structures
Single crystals of compound 1 (CCDC 752663) were obtained
from ethanol solution, while compound 2 (CCDC 752665) was
co-crystallized with cobalt dichloride hexahydrate also from etha-
nol. Single crystals of compound 3 (CCDC 795948) developed in di-
methyl sulfoxide and ethanol solution (1 v/1 v). All the crystals
were grown by slow evaporation of the solvent, at a temperature
of about 293 K. X-ray data were collected on a Bruker-Nonius Kap-
paCCD diffractometer using MoK
a radiation. The phase problem
was solved by direct methods using SIR30 and refined by full matrix
least-squares method using SHELX97.31 Hydrogen atoms were lo-
cated in difference Fourier maps and refined isotropically, using
riding model.
2. Results and discussion
The details of the crystal data, data collection and refinement
are listed in Table 1, while the asymmetric units of these structures
together with atom numbering are shown in Figure 3. All projec-
tions were generated using ORTEP.32
2.1. Chemistry
Synthesis of studied scaffolds is depicted in Scheme 1.
NHAc
NO2
O
1. H2/Pd
HNO3/H2SO4
2.AcO2
K2Cr2O7
O
5 °C
0-
N
AcHN
N
O2N
N
NH
N
OH
HO
OAc
OH
O
1
O
OH
O
OH
O
HCl
HO
N
NH2
2
CO2
O
N
N
3
OH
OH
OH
Scheme 1. Synthesis of quinolines 1–3.

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Table 1
Crystal data, measurement and calculation details
Chemical formula
Structure 1
12H10N2O3
Structure 2
Structure 3
C
2[C11H8NO3ÁHCl]ÀÁ
[C11H10NO3]+ÁClÀ
[Co(H2O)4]2+
Crystal data
M (g molÀ1
Crystal system
Space group
a [Å]
b [Å]
c [Å]
)
230.339
Triclinic
P1
304.14
239.759
Triclinic
P1
Triclinic
ꢀ
ꢀ
ꢀ
P1
3.864(3)
11.545(1)
14.049(1)
104.33(3)
94.16(2)
92.45(5)
604.43(9)
2
7.274(3)
7.413(3)
11.874(6)
91.38(2)
103.40(2)
94.75(2)
620.10(5)
2
7.207(1)
9.470(2)
9.639(2)
97.21(1)
109.52(1)
108.12(1)
569.64(2)
2
a
[°]
b [°]
c
[°]
V [Å3]
Z
D [g cmÀ3
F (0 0 0)
l
]
1.265
240
0.093
1.629
313
0.968
1.502
268
0.338
[mmÀ1
]
Data collection
hmin, hmax
kmin, kmax
À5, 5
À9, 9
À9, 9
À15, 15
À15, 18
3.58–27.67
3665
À9, 9
À12, 12
À12, 12
1.00–27.48
5054
lmin, lmax
À15, 15
2.76–27.51
4855
H
range [°]
Unique reflns
Reflns F0 > 4d(F0)
2667
2825
2615
Refinement
R1 for F0 > 2d(F0)
R1 for all data
wR2 for F0 > 2d(F0)
GOOF on F2
0.0847
0.1790
0.2539
1.032
0.0605
0.0893
0.1324
1.020
0.0376
0.0462
0.1084
1.059
2.2.1. Molecule 1
The asymmetric unit of 1 consists of one molecule (Fig. 3(1)). The
bond lengths C7–C8 and C5–C10 are 1.354(5) Å and 1.377(5) Å,
respectively, and they are shorter than typical CAr–CAr distances.33
The C6–O1 and C9–O2 bonds demonstrate double character, which
suggest electron localisation of quinolinedione arrangement of the
ring. The valence angles C5–C6–C7 = 118.4(3)° and C8–C9–
C10 = 118.5(3)° are smaller than 120°, which can be ascribed,
according to VSEPR theory, to the influence of oxygen free electron
pairs and C–O double bonds. The high values of the atomic displace-
ment parameters for the methyl group and for oxygen can be ex-
plained by the rotational freedom (O3) and certain possibility of
disorder (O1, O2). The ring system of the molecule 1 is almost pla-
nar and coplanar with the substituents, the greatest distortion,
0.107(5) Å, being that of the O3 atom. Also torsion angles, C10–
C5–C6–O1 = 177.8(4)°, C7–C8–C9–O2 = À179.6(4)°, C7–C8–N2–
C11 = À3.3(7)°, C8–N2–C11–O3 = À1.2(7)°, C8–N2–C11–C12 =
À179.6(4)°, confirm planarity of the whole molecule. The packing
of the molecules in the unit cell is dominated mainly by hydrogen
Figure 3. ORTEP projection of the asymmetric units of structures 1–3.
Table 2
Hydrogen bonds geometry in the crystal structure of 1
bonds and p–p interactions. The details of hydrogen bond geometry
are given in Table 2. The proton of N2 atom is shared by two oxygen
atoms with formation of a bifurcated hydrogen bond. The intermo-
lecular contact N2–H2Á Á ÁO2 represents rather a weak hydrogen
bond interaction as shown by the donor–acceptor distance
(Table 2).
D–H
A
d(D–H) [Å]
d(HÁ Á ÁA) [Å]
2.33(4)
2.33(4)
\ DHA [°]
d(DÁ Á ÁA) [Å]
3.15(4)
2.63(1)
N2–H2
N2–H2
O2i
O2
0.83(4)
0.83(4)
176(3)
102(3)
Symmetry codes (i) Àx + 3, Ày, Àz + 1.
This situation is most probably caused by the steric hindrance
introduced by methyl groups. Intramolecular N2–H2Á Á ÁO2 hydro-
gen bond is another example of weak interaction because it leads
2.2.2. Molecule 2
The asymmetric unit of 2 consists of one molecule 2, protonated
at N1, one chloride anion, the cobalt cation and two water mole-
cules (Fig. 3(2)). Since the Co2+ position is that of the inversion cen-
tre (1/2, 1/2, 1/2), this ion is present at half-occupancy. Water
molecules linked with the cobalt cation show the highest atomic
displacement parameters because of their disorder.
to formation of a strained pentagonal ring. There are also
p–p
interactions in structure of 1 as shown by the distance between
centroids of neighbouring rings, which is 3.864(3) Å. This distance
is equal to the unit cell parameter a, which shows that the ‘sheets’
of molecules 1, parallel to (1 0 0) planes, are densely stacked in the
crystal.

K. Majerz-Maniecka et al. / Bioorg. Med. Chem. 19 (2011) 1606–1612
1609
O
N
HY
O
O
H
Mg2+
O
N
O
O
O
N
O
O
Asp 64
Asp 116
Figure 5. Hypothetical mechanism of quinoline derivative—magnesium cation
interaction35 at the active site of HIV integrase. HY-hydrophobic moiety.
The bond lengths, bond angles and torsion angles are compara-
ble to those typical for similar compounds.23
The relatively high value of C2–N1–C10 angle, equal to
123.9(3)°, is most probably the result of N1 protonation.
The coordination sphere of the cobalt cation is occupied by the
oxygen atoms belonging to four water molecules and two mole-
cules 2 (Fig. 4).
Figure 4. Cobalt cation environment.
Table 3
Hydrogen bonds geometry in the crystal structure of 2
The O–Co–O angles are approximately equal to 90°, which leads
to octahedral environment of Co. Crystal structure of 2 is stabilized
by seven hydrogen bonds. The details of their geometry are given
in Table 3.
Intramolecular O6–H61Á Á ÁO712 hydrogen bond is a weak inter-
action because it is strained by its participation in the six-mem-
bered ring which consist of C6, O6, H61, O72, C71 and C7.
Intermolecular O11–H111Á Á ÁO712i and O11–H11Á Á Á1O711i inter-
actions are bifurcated, and similar situation can be observed for
D–H d(D–H) [Å] d(HÁ Á ÁA) [Å] \ DHA [°] d(DÁ Á ÁA) [Å]
A
O11–H111 O712i
O11–H111 O711i
O12–H121 O711i
O12–H122 O711ii 0.89(2)
O11–H112 O12
0.88(2)
0.88(2)
0.91(2)
2.42(4)
2.52(7)
2.56(8)
2.11(6)
2.42(4)
2.21(4)
1.70(5)
113(3)
120(6)
133(9)
129(6)
118(3)
168(4)
151(5)
2.88(5)
3.06(6)
3.25(7)
2.75(6)
2.94(1)
3.11(4)
2.49(4)
0.89(2)
0.91(4)
0.87(5)
N1–H1
Cl3
O6–H61
O712
i = Àx, Ày, Àz; ii = x, y + 1, z + 1.
a
NH+
b
Cl
HO
O
O
Co2+
O
O
HO
Cl
NH+
Figure 6. (a) Fragment of the crystal structure of 2 showing the coordination of Co cation and mutual p–p interactions between quinoline moieties of two complexes. (b)
Scheme of cobalt cation interactions with carboxyl oxygen atoms.

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Table 4
Hydrogen bonds geometry in the crystal structure of 3
D–H
A
d(D–H) [Å] d(HÁ Á ÁA) [Å] \ DHA [°] d(DÁ Á ÁA) [Å]
N1–H1
O9–H9
O812–H812
O1W–H1W1 Cl
O1 W–H1W2 Clii
O1 W 0.83(2)
O811 0.89(2)
2.01(2)
1.81(2)
2.13(2)
2.31(2)
2.39(2)
2.830(2)
2.590(2)
2.965(1)
3.168(1)
3.282(1)
166(2)
146(2)
161(2)
177(2)
170(2)
Cli
0.87(2)
0.86(2)
0.90(2)
i = x + 1, y + 1, z + 1; ii = Àx À 1, Ày + 1, Àz + 2.
O711i oxygen atom, which is an acceptor for two hydrogen atoms,
H111 and H121. The strongest interaction is N1–H1Á Á ÁCl3, where
the chloride anion is the hydrogen acceptor.
Two molecules 2, that coordinate cobalt cation, form a dimer,
which is stabilized by the p–p interactions. The distance between
centroids of quinoline ring is 4.00(3)Å.
Since the crystal structure of the salt 2[C11H8NO3ÁHCl]ÀÁ
[Co(H2O)4]2+ is very interesting from the viewpoint of its inhibitory
behaviour towards HIV integrase, it is described below in greater
detail.
There are two hypotheses about magnesium cation—quinoline
derivatives interactions at the active site of HIV integrase. Accord-
ing to the first of them one molecule of the inhibitor is in contact
with two metal cations,25–27,34 while according to the second
hypothesis one quinoline interacts with one Mg cation.23
In the pattern shown in Figure 5 one molecule of inhibitor is in
contact with magnesium cation via carboxyl and hydroxyl group,
in position 7 and 8 of the quinoline ring, respectively. There are
also two aspartic acid moieties (Asp 64 and Asp 116) and two
water molecules in the octahedral Mg cation environment.
The model of interactions between the metal atom at the
integrase active site and the quinoline inhibitor, which we can de-
duce from the Co-model inhibitor interactions in the crystal struc-
ture of molecule 2 (Fig. 6) is different.
The cobalt cation interacts with the oxygen atoms, which be-
long to the deprotonated carboxyl groups of two quinoline moie-
ties, with Co–O distance equal 2.072(3) Å. The hydroxyl group is
a proton donor in the intramolecular hydrogen bond, which stabi-
lizes the orientation of substituents coplanar with the quinoline
plane. It is interesting that, in spite of these differences, the Co–O
distance is equal to those characteristic for Mg–O (2.073(2) Å) in
magnesium–quinoline complex.34 In this context we postulate that
the cobalt cation might be a suitable model for prediction of the
magnesium cation interactions with its environment.
2.2.3. Molecule 3
The asymmetric unit of the third structure contains one mole-
cule 3, in the hydrochloride form, and one water molecule
(Fig. 3(3)). The bond lengths, bond angles and torsion angles are
comparable to those typical for similar organic compounds.33 The
hydroxyl and methyl group are coplanar with the quinoline ring,
the torsion angles C7–C8–C9–O9 and C4–C3–C2–C21 being
À179.8(1)° and À178.5(1)°, respectively. The carboxyl group is
deviated from planarity as shown by the C6–C7–C8–C81 angle va-
lue, À175.5(1)°. The packing of the molecules 3 in the crystal is
dominated mainly by hydrogen bonds, see Table 4 for details.
Intermolecular hydrogen bonds are formed between molecule 3
and water molecules, molecule 3 and the chloride anion and also
between the water molecule and chloride anion. Intramolecular
bond, O9–H9Á Á ÁO811, is weak because it leads to formation of
strained hexagonal ring.
Figure 7. Compounds 1–3 docked into HIV IN active site.
Crystal structure of 3 is also stabilized by p–p interactions be-
2.3. Molecular docking simulations
tween two quinolines, which are related via inversion centre. The
distance between C10 atom of one molecule to the centroid of
the neighbouring ring is 3.461(3) Å.
Molecular modelling and molecular mechanics simulations
were performed using the CCG MOE software packages running

K. Majerz-Maniecka et al. / Bioorg. Med. Chem. 19 (2011) 1606–1612
1611
Table 5
Selected interactions between studied compounds and HIV IN
41
Compound
IC50
[lM]
LdGa [kcal/mol]
Interactions with Mg2+
Interactions with aminoacids
Hydrogen bonding
O3–GlnA148
Through Mg2+
Indirect (allosteric)
1
2
3
77
À9, 67
O1–Mg
AspA64
GluA152
AspA64
GluA152
GluA152
AspA64
AspA116
CysA65
AspA116
AspA116
HisA67
4716
À18, 75
À14, 66
O6–Mg–O711
O6H–AspA64
O6H–GluA152
—
>10021
O9–Mg1–O812
O811–Mg
a
Calculated for the best docked pose of each structure.
on an Intel Pentium based machines with the GNU/Linux Debian
operating system. Molecules 1–3 were collected in the input set
and prepared for docking by standard procedure including the
structure optimisation using the MMFF94x forcefield and calcula-
tion of the partial atomic charges using PM1 algorithm. Protomers
and tautomers for these compounds were generated. Protein struc-
ture of HIV-1 integrase (full length DNA–integrase complex) was
obtained from 1WKN PDB entry containing two aminoacid chains
and two Mg2+ ions per each chain, bonded to ASP64, ASP116 and
GLU152 residues. Additionally into the enzyme two strands of the
viral DNA, segments: 1–25 and 26–5236 has been docked. The
integrase structure was prepared for docking by addition of missing
hydrogen atoms, protein desolvatation, the calculation of the atom-
ic partial charges (AMBER99 forcefield) and the protonation of the
protein at physiological pH 7.4 using the PROPKA related method.37
During docking a series of poses (ligand–protein complexes of par-
ticular conformation and mutual orientation) was generated for
each molecule. The used alpha triangle docking algorithm consisted
in alignment of triplets of ligand atoms on triplets of protein site
points which are the centres of alpha spheres38 created in the po-
tential binding sites. During the simulation the poses were gener-
ated in sequence from a single conformer (protomer, tautomer)
by applying a collection of preferred torsion angles to the rotatable
bonds. The last stage of docking procedure was the energy minimi-
sation and geometry optimisation of each docked pose in the bind-
ing site conditions. Classification of docking results was realized
using London dG (LdG) scoring function (SF) which estimates the
free energy of the ligand binding. A set of the highest scored poses
were chosen for each molecule (pose) docked.39
actions in case of 1 and 2 is different from that observed in case of
3. At the same time, compound 2 binds very efficiently and inter-
acts with two aminoacids AspA64 and GluA152 by means of hydro-
gen bonding. Compound 1 binds relatively weakly to one Mg2+
cation and interacts with GlnA148. On this basis we can suggest
different interactions pattern for structures 2 and its isomer 3.
3. Conclusions
Three small molecular scaffolds used for fragment-based design
of new HIV IN inhibitors were synthesized. Their crystal structures
and in vitro activities were collected and molecular docking of
studied compounds was performed. Some differences in the
molecular interactions between inhibitors and enzyme seem to
elucidate the activity pattern. Most active scaffold of 5-hydroxy-
quinaldine-6-carboxylic acid was found to be more efficient in
hydrogen bonding interactions with enzyme active site than other
two compounds. Further optimisation of this scaffold may lead to
new interesting inhibitors.
Acknowledgements
This work was supported in part by KBN Grant PB1942/H03/
2006/31 to K.M.-M. Molecular modelling was supported from PB
N519 575638.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bmc.2011.01.045. These data
include MOL files and InChiKeys of the most important compounds
described in this article.
According to some reports the scoring functions assessing
molecular docking simulations should not be quantitatively corre-
lated with activity.40 Thus, in Figure 7 we present the two-dimen-
sional ligand–receptor interaction diagrams which allows us to
qualitatively observe binding in the presence of ligands.
References and notes
This depicts relatively strong connections or hydrogen bonds as
well as electrostatic or charge-transfer interactions between the li-
gand and the respective aminoacid residues. In Table 5 we have
shown the interactions between ligand and protein in complex
along with scoring functions and biological activities of the studied
compounds. Activities are relatively low when compared to the
leading structures described in literature. However, in case of frag-
ment-based design this level of activity is quite promising for fur-
ther optimisation. Nevertheless compound 3 can be regarded as
inactive while 1 and 2 are moderately active. Further insight into
the data collected in Table 5 provides some interesting remarks.
When compared only by scoring function, the scaffold 2 was
docked at the active site with the lowest energy which can be as-
cribed to its high affinity, no doubt influencing the activity. Then 8-
hydroxy-2-methylquinoline-7-carboxylic acid (3) seems to be
favourably docked into the active site of HIV IN with strong inter-
actions with two metal cations. On the other hand, it does not bind
directly to aminoacids. Furthermore, the pattern of allosteric inter-
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