Novel indole based NNRTIs with improved potency against wild type and resistant HIV

Article abstract of DOI:10.1016/j.bmcl.2014.08.020

The human immunodeficiency virus (HIV) pandemic remains a significant problem, especially in developing nations where the social and economic impacts are severe. Until a cure or vaccine for the disease is found, a constant supply of new compounds to fill the drug development pipeline is a requirement, given the tendency for the virus to rapidly develop resistance to current therapies. Here we disclose our efforts to improve upon the efficacy of cyclopropyl-indole derivatives developed as NNRTIs in our laboratories. To this end, modifications to the functionality occupying the small Val179 pocket have resulted in nearly two orders of magnitude increase in potency.

Full text of DOI:10.1016/j.bmcl.2014.08.020

Bioorganic & Medicinal Chemistry Letters 24 (2014) 4376–4380
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Novel indole based NN.RTIs with improved potency against wild type
and resistant HIV
a
a
b
a
a
b
Ronel Müller , Iqbal Mulani , Adriaan E. Basson , Nicole Pribut , Mohammad Hassam , Lynn Morris ,
a
a,
⇑
Willem A. L. van Otterlo , Stephen C. Pelly
a
Department of Chemistry and Polymer Science, Stellenbosch University, Private Bag X1, 7602 Matieland, Western Cape, South Africa
AIDS Virus Research Unit, National Institute for Communicable Diseases, Private Bag X4, Sandringham 2131, Johannesburg, South Africa
b
a r t i c l e i n f o
a b s t r a c t
Article history:
The human immunodeficiency virus (HIV) pandemic remains a significant problem, especially in devel-
oping nations where the social and economic impacts are severe. Until a cure or vaccine for the disease is
found, a constant supply of new compounds to fill the drug development pipeline is a requirement, given
the tendency for the virus to rapidly develop resistance to current therapies. Here we disclose our efforts
to improve upon the efficacy of cyclopropyl-indole derivatives developed as NNRTIs in our laboratories.
To this end, modifications to the functionality occupying the small Val179 pocket have resulted in nearly
two orders of magnitude increase in potency.
Received 13 July 2014
Revised 5 August 2014
Accepted 6 August 2014
Available online 13 August 2014
Keywords:
HIV
NNRTIs
AIDS
Ó 2014 Elsevier Ltd. All rights reserved.
Indole
The human immunodeficiency virus pandemic is undoubtedly
one of the worst to afflict mankind, with over 33 million infected
individuals, most of which are inhabitants of poorer developing
nations.1 Following an acute stage of infection, HIV infected indi-
viduals usually show a marked decline in CD4 lymphocyte num-
bers, with a concomitant deterioration of their immune system.
Left untreated, the HIV infection progresses to a condition known
as acquired immunodeficiency syndrome (AIDS), as opportunistic
relatively non-polar compounds and are non-competitive inhibitors
of the HIV enzyme reverse transcriptase (RT). Given their excellent
therapeutic index in comparison to some of the other classes of
,2
8,9
anti-HIV agents, NNRTIs are utilised in front line treatment, as
well as in individuals requiring more specialised treatment due
to complications arising from resistant strains of the virus.10 How-
ever, resistance is an ongoing problem, and with the unfortunate
discontinued development of promising clinical trial candidates
3
11
12
infections develop. A drastic decline in the general health of the
such as lersivirine, and IDX-899, there is a need to resupply
the NNRTI drug development pipeline (Fig. 1). Our past research
involved developing novel cyclopropyl-indole derivatives as
NNRTIs, which were designed using molecular modelling. Several
of these compounds (e.g., 1 and 2) were found to be slightly more
afflicted person is observed, ultimately leading to death. Fortu-
nately, as a result of a significant amount of research, therapeutic
intervention has changed the picture for HIV infected individuals
4
and although the disease cannot be cured, it can be controlled.
A complicating factor however arises in that the virus has a high
mutation rate and this readily leads to the emergence of resistant
strains, thereby undermining current therapeutic intervention. For
example, the K103N mutation is the major contributor to patients
failing first line treatment, rendering the non-nucleoside reverse
transcriptase inhibitors (NNRTIs) nevirapine (NVP) and efavirenz
potent than nevirapine (IC50 ꢀ 0.1
lM) in our phenotypic assays.
Here we disclose our endeavours to significantly improve upon
these potencies, and to optimise the compounds against resistant
strains of the virus.
In our initial efforts to improve upon these compounds, we
decided to retain the cyclopropyl moiety at the indole’s 3-position,
as molecular modelling studies had indicated that this group was
well suited to the small hydrophobic pocket located in the vicinity
5
,6
(
EFV) ineffective.
Given the constant need to develop new anti-HIV agents to
1
3
overcome resistance issues and effectively control viral levels in
HIV infected individuals, we have focussed our attention on devel-
oping novel indole based NNRTIs.7 NNRTIs are typically small,
of Val179 (Fig. 2). Therefore, we turned our attention to finding a
suitable replacement for the ester located the indole’s 2-position.
Although the carbonyl of the ester functionality is well positioned
to facilitate a second hydrogen bonding interaction to Lys101, the
hydrophobic ethyl chain is somewhat of a mismatch, as this pro-
trudes out of the non-nucleoside inhibitor binding pocket (NNIBP)
⇑
Corresponding author. Tel.: +27 21 808 2180; fax: +27 21 808 3360.
E-mail address: scpelly@sun.ac.za (S.C. Pelly).
http://dx.doi.org/10.1016/j.bmcl.2014.08.020
960-894X/Ó 2014 Elsevier Ltd. All rights reserved.
0

R. Müller et al. / Bioorg. Med. Chem. Lett. 24 (2014) 4376–4380
4377
Having been dissuaded from modifying the ester functionality
we now turned our attention to the binding contributions
made by the cyclopropyl group and the aryl moiety attached at the
CN
NC
O
P
O
O
3
-position of the indole. In the synthesis of these analogues, the
Cl
Cl
N
NH2
formation of the cyclopropyl group was the one problematic reac-
tion, being modest yielding, and difficult to reproduce. Moreover,
we discovered during the course of synthesising various analogues
that our methodology to install the cyclopropyl group was ineffec-
tive without the ester group at the 2-position on the indole,
thereby limiting the scope of our intended library. Thus, in a small
SAR study we first investigated the effect of removing the hydro-
phobic group occupying the Val179 pocket. To this end we syn-
thesised the indole derivative 11, easily attainable by our
acylation methodology, followed by defunctionalisation of the car-
bonyl 8 (Scheme 2). As expected, a deterioration in potency was
observed, indicative that the cyclopropyl group had some benefi-
cial role in the binding of the inhibitor. However, removal of the
phenyl functionality completely as in compound 12 had a signifi-
N
OH
N
NC
Lersivirine
O
H
IDX-899
Ph
Cl
S
CO
2
Et
2
CO Et
N
N
1
H
2 H
IC50 = 85 nM
IC50 = 65 nM
Figure 1. Promising drug candidates lersivirine and IDX-899 recently removed
from clinical trials, and our past research aimed at developing novel indole-based
NNRTIs.
Val179
Leu234
7
Cl
Cl
cant detrimental effect to the potency. This lends testimony to
the importance of the
p–p stacking of the aryl group to Tyr181.
Tyr181
As an extension of this study, the nitrile derivative 13 was synthes-
ised by way of a Mannich reaction, followed by alkylation and sub-
stitution with the cyanide ion. This new structure lacks the
functionality to occupy the small Val179 pocket and does not effec-
tively interact with Tyr181. Therefore as expected, 13 performed
particularly poorly in our NNRTI phenotypic assay.
N
N
H
N
O
O
H
H
N
O
O H
O
O
O
O
H
mismatched
interaction
O
H
H
O H
H
H
O
H
H
R
R
matched
interaction
O
H
Lys101
Ph
1
4
2
0.712
3.9
5
6
Having established the importance of the phenyl group at the
Cl
R
R = -OEt -O(CH ) OH -NH(CH ) OH -NHNH
2
2
2
2
3
-position of the indole, we now turned our attention to of the
IC50 (uM) = 0.085
cLogP = 4.8
0.209
3.4
4.40
2.8
problematic cyclopropyl ring system, with the intention of moving
toward more easily attainable bioisosteres. The most obvious
change would be to switch to a dimethyl system as in compound
14 (Fig. 3). However, molecular modelling studies indicated that
the Val179 pocket would not be wide enough to accommodate
both methyl groups, set about a somewhat more tetrahedral ter-
tiary carbon in comparison to the cyclopropyl system 1. Therefore,
in a series of analogues evaluated by docking and binding energy
calculations, the acyclic ethyl and methyl-ether analogues (15
and 16, respectively) appeared promising. In fact, these com-
pounds performed even better in terms of binding energy and
docking score calculations than the original cyclopropyl derivative
1. Molecular modelling studies also suggested no strong preference
for a specific enantiomer, as both the R and S configurations of 15
and 16 would be well accommodated in the Val179 pocket with a
slight shift of the phenyl substituent.
N
H
O
Figure 2. Our initial endeavours to improve potency by addressing the mismatched
hydrophobic-hydrophilic interactions as the NNIBP entrance actually resulted in
compounds with significantly poorer potency.
into the solvation region. Thus, the most obvious change was to
incorporate a suitable polar group at the end of the chain to inter-
act with the water.
To this end we synthesised analogues 4–6 (Scheme 1). In this
process, direct trans-esterification or amidation proved problem-
atic given the stabilising effect of the indole on the ester. In our
hands, the synthesis was most effectively accomplished by the
two-step process of ester hydrolysis, followed by pyBOP mediated
coupling of the resulting carboxylic acid 3 with the corresponding
amine, alcohol or hydrazine.
These compounds were then evaluated in
a
phenotypic
Synthetically, we envisaged that the methyl ether derivative 16
could easily be attained from the ketone 18 (Scheme 3), an inter-
mediate in the synthetic strategy for obtaining the cyclopropyl sys-
1
4–16
assay,
and given the favourable modelling results, coupled
with the fact that the compounds now exhibited somewhat more
desirable cLogP values (with the exception of 6), we were disap-
pointed to find that they were actually significantly less potent
than their hydrophobic ethyl counterpart 1 (Fig. 2). Given that 4
and 5 are still somewhat lipophilic (cLogP ꢀ 3.6) we deemed it
unlikely that the modifications seriously affected membrane per-
meability. In fact a similar strategy has been employed by Silvestri
et al. in their extensive research on indolyl aryl sulfones and good
potency was retained when a polar chain was extended into the
7
tem. Indeed, after protecting 18 to afford 22, borohydride
reduction, followed by acid-mediated substitution of the resulting
hydroxyl functionality provided the protected derivative 31 in
good yield. Finally, base mediated deprotection of the indole
provided 16.
Evaluation of racemic 16 in a phenotypic assay revealed that as
suggested by molecular modelling, the methyl ether derivative was
significantly more potent than the cyclopropyl derivative
1
1
7
solvation region.
Therefore, our observed deterioration in
(Table 1). Interestingly, the somewhat larger ethyl-ether derivative
potency in converting 1 to 4 or 5, remains intriguing.
36 was also potent in the phenotypic assay, but the lack of an alkyl
Ph
Ph
OH
Ph
Cl
OEt
Cl
Cl
R
4 R= -O(CH2)2OH
5 R= -NH(CH ) OH
a
b
2
2
6
R= -NHNH2
N
H
O
N
H
O
N
H
O
1
3
2 2 2 2 2 2 2
Scheme 1. Reagents and conditions: (a) KOH, EtOH, 4 h, 80 °C, then HCl, 81%; (b) PyBop, HOBt, HO(CH ) OH, H N(CH ) OH or NH NH , DIPEA, corresponding amine or
alcohol, DMF, 2 h, rt, 60–85%.

4
378
R. Müller et al. / Bioorg. Med. Chem. Lett. 24 (2014) 4376–4380
O
IC50 (µM)
Ph
CO
Ph
CO
CC50 (µM)
Cl
Cl
0
.24
a
Et
b
Et
2
2
>100
N
N
H
8
9
11
Boc
O
CH
3
CH
3
Cl
Cl
Cl
Cl
Cl
Ref 7
Ref 7
2.25
4.3
CO
2
Et
CO
2
2
Et
Et
CO
2
2
Et
Et
4
N
H
N
H
N
H
7
12
13
NEt
2
CN
CO
c
d
19.8
25.5
CO
1
N
H
N
H
10
Scheme 2. Reagents and conditions: (a) benzoyl chloride, AlCl
MeOH, 18 h, 30 °C, 40% over two steps.
3 3 2 2
, DCE, 80 °C, 18 h, 86%; (b) TFA, Et SiH, DMF, 4 h, 0–30 °C, 32%; (c) Et NH, CH O, NaOH, 2 h, 30 °C; (d) MeI, KCN,
R
2
R
1
Ph
CO
Cl
2
Et
N
H
14 R
15 R
16 R
1
1
=Me, R
=Et, R =H
=OMe, R =H
2
=Me
2
1
2
Figure 3. Ethyl or methyl-ether analogues are well accommodated in the small Val179 pocket and in fact result in better docking scores and binding energy values than the
corresponding cyclopropyl derivatives. Molecular modelling indicates only a slight preference for the R enantiomer (orange) in comparison to the S enantiomer (white).
O
O
HO
R
2
R
2
R
2
Cl
Cl
Cl
Cl
a
b
c
c
R
1
R
1
R
1
R
1
N
H
2
Et
N
N
R
N
H
3
R
3
7
R
1
=CO
1
1
8 R
9 R
0 R
1 R
1
1
=CO
=CO
=H, R
=H, R
2
2
Et, R
Et, R
=Ph
=mXyl
2
2
=Ph
22 R
1
1
=CO
2
2
Et, R
Et, R
=Ph, R
=mXyl, R
2
2
=Ph, R
=mXyl, R
=Tosyl
=Boc
3
=Tosyl
26 R
27 R
28 R
29 R
1
=CO
=CO
=H, R
=H, R
2
2
Et, R
Et, R
=Ph, R
=mXyl, R
2
2
=Ph, R
=mXyl, R
=Tosyl
=Boc
3
=Tosyl
1
7 R =H
1
=mXyl
23 R
24 R
25 R
=CO
3
=Boc
1
3
=Boc
2
1
1
2
2
1
1
=H, R
2
2
3
1
1
2
2
3
2
=H, R
3
3
30 R
1
=CO
2
2 3
Et, R =Ph, R =H
O
4
O
N
O
R
R
2
Ph
Ph
Cl
Cl
Cl
CF3
Cl
CF3
d
e
f
R
1
S
S
O
O
N
N
O
O
H
R
3
37 Tos
38
f/g
3
1 R
2 R
3 R
4 R
5 R
1
1
=CO
2
Et, R
Et, R
Et, R
=Ph, R
=mXyl, R
2
2
=Ph, R
=Ph, R
=mXyl, R
=Tosyl, R
=Boc, R
3
3
=Tosyl, R
= Boc, R
=Boc, R
=Me
=Me
4
=Me
=Et
=Me
3
3
3
3
=CO
2
2
4
O
R
4
1
1
=CO
2
3
4
R
2
1
6 R
=CO
=CO
=CO
Et, R
Et, R
Et, R
=Ph, R
=Ph, R
=Ph, R
=mXyl, R
=Me
=Me
=Et
=Me
1
2
2
4
=H, R
=H, R
2
3
4
36 R
1
2
2
4
1
2
3
4
3
4
9 R
1
2
2
4
R
1
0 R
1
=H, R
2
4
Note:
mXyl = 3,5-dimethyl phenyl
N
H
41 R =H, R =mXyl, R =Me
1
2
4
Scheme 3. Reagents and conditions: (a) benzoyl chloride or 3,5-dimethylbenzoyl chloride, AlCl
= Tosyl; Boc O, DIEA, DMAP, THF, rt, 5 h, 82–84% when R = Boc; (c) NaBH , EtOH, rt, 18 h, 57–95%; (d) p-TsOH, MeOH or EtOH, rt, 18 h, 38–87%; (e) 34, LDA,
trifluoromethanesulfonyl chloride, THF, À78 °C, 20 min, 78%; (f) K CO , MeOH, reflux, 3 h when R = Boc or KOH, THF, rt 18 h, when R = Tosyl; (g) K PO , MeOH or EtOH,
0 °C, 4 h, 90–99% R = Boc.
3
, DCE, 30 °C, 4 h, 72–86%; (b) p-TsCl, NaH, DMF, rt, 18 h, 81–85% when
R
3
2
3
4
2
3
3
3
3
4
7
3
group in this position (compound 30) had a serious detrimental
effect to the potency.
Having optimised the functionality occupying the small Val179
pocket, we now returned to looking at the ester located at the
2-position of the indole, as we were concerned about the lability
of this group in vivo. Noteworthy is the fact that according to the
modelling studies, the carbonyl of the ester group facilitates
an important electrostatic interaction with the amide backbone

R. Müller et al. / Bioorg. Med. Chem. Lett. 24 (2014) 4376–4380
4379
Table 1
portion of Lys101, and this particular feature we wished to retain.
Having considered a number of bioisosteres, including small het-
erocyclic systems located at this position, the most promising func-
tional group modification appeared to be a sulfone located at this
position. A particular benefit of this group over the ester function-
ality was the improved angle of the hydrogen bond between the
sulfone oxygen and the amide of Lys101 (Fig. 4). The preferred pla-
nar orientation of the ester carbonyl group with the indole system
is detrimental to this hydrogen bonding interaction, but by utilis-
ing a sulfone, it appeared that this problem would be overcome.
Synthesis of sulfone 38 required a slightly different strategy to
our current route, beginning with the more sparsely functionalised
Evaluation of target compounds by phenotypic assay against wild type HIV-1 (IC50
and cellular toxicity values (CC50
)
)
R
3
R
2
Cl
R
1
N
H
Indole
R
1
R
2
R
3
IC50
M)
CC50
M)
(l
(
l
16
30
36
38
39
40
41
CO
CO
CO
SO
CO
H
2
2
2
Et
Et
Et
CF
Ph
Ph
Ph
Ph
OMe
OH
OEt
OMe
OMe
OMe
OMe
0.02
1.15
0.03
1.20
0.03
2.43
0.30
0.12
25.3
22.7
22.8
24.2
36.5
67.0
67.7
2
3
5
-chloroindole 17 (Scheme 3). A Friedal–Crafts acylation intro-
2
Et
3,5-Dimethylphenyl
Ph
3,5-Dimethylphenyl
duced the required phenacyl substituent at the 3-position of the
indole, forming 20. Protection of the indole nitrogen, followed by
reduction of the ketone 24 and then acid mediated substitution
to introduce the methyl ether afforded the near final derivate 34.
Directed ortho metallation, mediated by the tosyl protecting group
then paved the way for the installation of the trifluoromethane sul-
fonyl functionality, providing 37. Finally, the key hydrogen bond
donor indole nitrogen was once again revealed after deprotection,
affording 38. In the evaluation of 38 we were rather surprised to
discover that in contrast to the results suggested by modelling, this
H
Nevirapine
compound performed poorly, with an IC50 value of 1.2
Table 1).
Having settled on 16 as the most potent compound in this ser-
lM
(
ies, we now focused our attention on derivatives that would
improve the performance against common resistant strains of
the virus. Typically, for the aryl ring system located in the
Tyr181/188 pocket, 3,5-disubstituted phenyl rings show improved
potency against resistant strains of the virus. Methyl, nitrile and
chloro-substituents are often utilised in this case.8
,17,18
To this
end, analogue 39 was synthesised starting from ethyl 5-chloro-2-
indolecarboxylate 7, and 3,5-dimethylbenzoyl chloride, itself
readily obtainable from the corresponding acid (Scheme 3).
With both compounds in hand, we now compared their activi-
ties against a range of mutant strains in a phenotypic assay
(
Chart 1). Clearly evident was the fact that across all mutant strains
Figure 4. The sulfone (in orange) located at the 2-position of the indole was a
promising replacement for the ester (in green), and in fact appeared to have better
hydrogen bonding characteristics to the amide of Lys101.
the dimethyl analogue 39 was significantly more potent than the
unsubstituted phenyl variant, 16, although these two compounds
performed very similarly against the wild type virus (in fact, 16
Chart 1. Decrease in potency expressed as fold change values for compounds 16 and 39, evaluated against a panel of mutant HIV viral strains.

4
380
R. Müller et al. / Bioorg. Med. Chem. Lett. 24 (2014) 4376–4380
is slightly more effective here). Of particular interest are the results
of 16 and 39 when assayed against HIV-1 viruses with prevalent
NNRTI resistance mutations. Lead compound 16 was found to be
ineffective against the V106M mutation, which causes resistance
to EFV. However, the dimethyl variant, 39, remained effective.
The Y181C mutation, which renders NVP ineffective, was found
to be problematic for both compounds, no doubt as a result of
involvement in this project, and to the Centre for High Performance
Computing (CHPC) for providing access to Accelrys Discovery
Studio.
References and notes
1.
Gupta, R. K.; Jordan, M. R.; Sultan, B. J.; Hill, A.; Davis, D. H. J.; Gregson, J.;
Sawyer, A. W.; Hamers, R. L.; Ndembi, N.; Pillay, D.; Bertagnolio, S. Lancet 2012,
the dependence on the aryl
p–p stacking with Tyr181. Neverthe-
3
80, 1250.
2. Prajapati, D. G.; Ramajayam, R.; Yadav, M. R.; Giridhar, R. Bioorg. Med. Chem.
009, 17, 5744.
less, 39 was still significantly more potent than 16. The G190A
mutation also causes resistance to NVP but both compounds 16
and 39 remain effective, with some reduction in potency. The most
exciting result however was obtained when 16 and 39 were eval-
uated against the most prevalent and particularly problematic
front line mutation, K103N. Here indole 39 remained effective, dis-
playing only slightly reduced potency, while intermediate and high
levels of resistance were displayed towards 16 and NVP,
respectively.
2
3.
Reynolds, C.; de Koning, C. B.; Pelly, S. C.; van Otterlo, W. A. L.; Bode, M. L. Chem.
Soc. Rev. 2012, 41, 4657.
4. De Clercq, E. Int. J. Antimicrob. Agents 2009, 33, 307.
5.
Hamers, R. L.; Sigaloff, K. C. E.; Wensing, A. M.; Wallis, C. L.; Kityo, C.; Siwale,
M.; Mandaliya, K.; Ive, P.; Botes, M. E.; Wellington, M.; Osibogun, A.; Stevens,
W. S.; Rinke de Wit, T. F.; Schuurman, R.; Resistance, T. P. A. S. T. E. Clin. Infect.
Dis. 2012, 54, 1660.
6. Antinori, A.; Zaccarelli, M.; Cingolani, A.; Forbici, F.; Rizzo, M. G.; Trotta, M. P.;
Di Giambenedetto, S.; Narciso, P.; Ammassari, A.; Girardi, E.; De Luca, A.; Perno,
C. F. AIDS Res. Hum. Retroviruses 2002, 18, 835.
Finally, to evaluate the importance of the ester at the 2-position,
we synthesised analogues 40 and 41 (Scheme 3), which lack the
hydrogen bond acceptor functionality at the indole’s 2-position.
As expected, these compounds were significantly less potent than
their counterparts 16 and 39, highlighting the benefits of maintain-
ing this interaction.
7
.
Hassam, M.; Basson, A. E.; Liotta, D. C.; Morris, L.; van Otterlo, W. A. L.; Pelly, S.
C. ACS Med. Chem. Lett. 2012, 3, 470.
Li, D.; Zhan, P.; De Clercq, E.; Liu, X. J. Med. Chem. 2012, 55, 3595.
Balzarini, J. Curr. Top. Med. Chem. 2004, 4, 921.
8
9
.
.
10. Martins, S.; Ramos, M. J.; Fernandes, P. A. Curr. Med. Chem. 2008, 15, 1083.
11. Mowbray, C. E.; Burt, C.; Corbau, R.; Gayton, S.; Hawes, M.; Perros, M.; Tran, I.;
Price, D. A.; Quinton, F. J.; Selby, M. D.; Stupple, P. A.; Webster, R.; Wood, A.
Bioorg. Med. Chem. Lett. 2009, 19, 5857.
In conclusion, guided by molecular modelling we have signifi-
cantly improved upon our original cyclopropyl indole NNRTIs by
improving interactions within the small Val179 pocket. Further-
more, a 3,5-dimethylsubstituted analogue has shown marked
improvements in potencies across a panel of resistant strains, espe-
cially the problematic K103N mutant.
1
2. Storer, R.; Alexandre, F.-R.; Dousson, C.; Moussa, A.; Bridges, E.
Enantiomerically pure phosphoindoles as HIV inhibitors. Patent Number:
WO2007US20900, 2007-09-28.
13. Molecular modelling studies were carried out using Accelrys Discovery Studio
4.0. The RT receptor utilised was obtained from the Protein Databank with PDB
ID 2RF2. Docking studies were performed using the CDocker protocol.
4. Gupta, R. K.; Kohli, A.; McCormick, A. L.; Towers, G. J.; Pillay, D.; Parry, C. M.
AIDS 2010, 24, 1651.
5. Parry, C. M.; Kohli, A.; Boinett, C. J.; Towers, G. J.; McCormick, A. L.; Pillay, D. J.
Virol. 2009, 83, 9094.
1
1
Acknowledgments
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The authors thank the National Research Foundation (NRF) and
the Medical Research Council (MRC) for funding this project.
We also express our gratitude to the NICD for their valuable