Discovery of N-(3-fluoro-4-methylsulfonamidomethylphenyl)urea as a potent TRPV1 antagonistic template

Article abstract of DOI:10.1016/j.bmcl.2016.06.010

A series of homologous analogues of prototype antagonist 1 and its urea surrogate were investigated as hTRPV1 ligands. Through one-carbon elongation in the respective pharmacophoric regions, N-(3-fluoro-4-methylsulfonamidomethylphenyl)urea was identified as a novel and potent TRPV1 antagonistic template. Its representative compound 27 showed a potency comparable to that of lead compound 1. Docking analysis of compound 27 in our hTRPV1 homology model indicated that its binding mode was similar with that of 1S.

Full text of DOI:10.1016/j.bmcl.2016.06.010

Bioorganic & Medicinal Chemistry Letters xxx (2016) xxx–xxx
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Discovery of N-(3-fluoro-4-methylsulfonamidomethylphenyl)urea
as a potent TRPV1 antagonistic template
Jihyae Ann a,y, Wei Sun b,y, Xing Zhou c, Aeran Jung a, Jisoo Baek a, Sunho Lee a, Changhoon Kim a,
Suyoung Yoon a, Sunhye Hong d, Sun Choi d, Noe A. Turcios e, Brienna K. A. Herold e, Timothy E. Esch e,
Nancy E. Lewin e, Adelle Abramovitz e, Larry V. Pearce e, Peter M. Blumberg e, Jeewoo Lee a,
⇑
a Laboratory of Medicinal Chemistry, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 151-742, Republic of Korea
b Shenyang Pharmaceutical University, Shenyang 110016, China
c Hainan Institute of Materia Medica, Haikou 570311, China
d National Leading Research Laboratory of Molecular Modeling & Drug Design, College of Pharmacy, Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul
120-750, Republic of Korea
e Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of homologous analogues of prototype antagonist 1 and its urea surrogate were investigated as
hTRPV1 ligands. Through one-carbon elongation in the respective pharmacophoric regions, N-(3-fluoro-
4-methylsulfonamidomethylphenyl)urea was identified as a novel and potent TRPV1 antagonistic
template. Its representative compound 27 showed a potency comparable to that of lead compound 1.
Docking analysis of compound 27 in our hTRPV1 homology model indicated that its binding mode was
similar with that of 1S.
Received 2 May 2016
Revised 2 June 2016
Accepted 6 June 2016
Available online xxxx
Keywords:
Ó 2016 Elsevier Ltd. All rights reserved.
Vanilloid receptor 1
TRPV1 antagonists
Analgesic
TRPV1 has emerged as a promising novel therapeutic target for
the management of chronic and inflammatory pain.1–3 Building on
initial insights provided by the prototypic ligands for TRPV1,
capsaicin4 and resiniferatoxin,5 our understanding of the structure
activity requirements for antagonistic ligands is maturing.6,7
Solution of the structure of TRPV1 by cryo electron microscopy8,9
antagonism of hTRPV1 activators including capsaicin, low pH, heat
(45 °C) and N-arachidonoyl dopamine (NADA). Recently we reported
that the
a-m-tolyl congener 2 showed high potency and selective
antagonism of capsaicin with a 3-fold improvement over prototype
1.18 Molecular modeling using our established hTRPV1 homology
model indicated that the enhanced potency of 2 might be attributed
to additional specific hydrophobic interactions of the m-tolyl group
with the receptor.
In continuation of our program to discover novel antagonistic
templates with the goal of developing clinical candidates for TRPV1
mediated neuropathic pain, we have investigated a series of one
carbon homologated analogues of prototype antagonist 1 and its
urea B-region surrogate 21 (Fig. 1). This homologation approach
can provide the optimal orientation of the three pharmacophoric
region by varying their positions. Of particular interest, the urea
B-region surrogates have an advantage over the corresponding
propanamide B-region antagonists previously reported12–19 in
terms of synthetic accessibility because the urea is achiral, unlike
the chiral propanamide, and the A-region amines, precursors for
urea coupling, are more commercially accessible.
and insights yielded by modeling10,11 provide
a powerful
complement guiding and validating the development of lead
therapeutic structures.
Over the last years, we have demonstrated that a series of
2-(3-fluoro-4-methylsulfonamidophenyl)propanamideswerepotent
hTRPV1 antagonists active against multiple activators.12–19 Their
structure activity relationship has been investigated extensively
based on the three pharmacophoric regions, designated the A-,
B-, and C-regions. In these investigations, compound
1 was
identified as a prototype antagonist, possessing 3-fluoro-4-methyl-
sulfonamidophenyl in the A-region, propanamide in the B-region,
and (6-trifluoromethyl-pyridin-3-yl)methyl in the C-region
(Fig. 1).12 Compound 1 exhibited highly potent and (S)-stereospecific
In this study, we synthesized one-carbon elongated analogues
in the respective A-, B-, C-regions and evaluated their binding
affinities and antagonism of hTRPV1 activation by capsaicin. With
⇑
Corresponding author. Tel.: +82 2 880 7846; fax: +82 2 762 8322.
E-mail address: jeewoo@snu.ac.kr (J. Lee).
These two authors contributed equally to this work.
y
http://dx.doi.org/10.1016/j.bmcl.2016.06.010
0960-894X/Ó 2016 Elsevier Ltd. All rights reserved.
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2
J. Ann et al. / Bioorg. Med. Chem. Lett. xxx (2016) xxx–xxx
F3C
F3C
F3C
F3C
F3C
R
H
H
N
H
N
N
N
B
F
N
N
F
N
NH2
N
CCl3
CN
C
a
b
O
S
O
O
S
O
N
N
O
N
N
O
N
O
A
N
H
1 R = Me
5
4
3
A = NH, CH2NH
c,d
N
2 R = Ph(3-Me)
B = CH-Me, NR, NHCH(R)
C = CH2, (CH2)2
F3C
F3C
F3C
Figure 1. Design of homologated congeners of prototype 1 as a TRPV1 antagonistic
N
OH
N
CN
NH2
template.
e,f
a
N
N
N
6
8
7
the optimized potent antagonistic template, we performed a dock-
ing study using our hTRPV1 homology model to analyze its binding
interactions with the receptor.
The syntheses of the C-region intermediates for coupling with
the A-region are shown in Scheme 1. The C-region amine 4 and
its N-trichloroacetyl derivative 5 were prepared from the nitrile 3
as previously reported.12
The one-carbon elongated analogue of 4 was also prepared from
3 by the conventional 5-step route. For the synthesis of the one-
carbon elongated C-region analogue of 1, the propionic acid 912
was converted to the corresponding pentafluorophenyl ester which
reacted with the amine 8 to provide 11 (Scheme 2).
Scheme 1. Synthesis of the C-region. Reagents and conditions: (a) BH3ꢀSMe2, THF,
reflux, 3 h; (b) Cl3CCOCl, TEA, CH2Cl2, rt, 3 h; (c) KOH, 80% aq EtOH, rt, 12 h (d)
LiAlH4, THF, rt, 14 h; (e) PBr3, CH2Cl2, rt, 3 h; (f) KCN, EtOH, reflux, 8 h.
O
H
F3C
N
S
O
O
RO
F
N
a,b
N
H
F
O
S
O
O
N
N
H
9
10
R=H
R=PFP
11
For the synthesis of the one-carbon elongated A-region analogue
of 1, thecommerciallyavailableamine12 was mesylatedand itsbro-
mide was substituted with ethyl propionate by a nickel-catalyzed
cross-coupling reaction20 to afford 14, which was hydrolyzed and
then coupled with the amine 4 to provide 16 (Scheme 3).
The B-region urea surrogate of 1 and its one-carbon elongated
C-region analogue, 21 and 22, respectively, were synthesized by
the coupling between the C-region amines and the phenylcarba-
mate 20, which was prepared from the commercially available
amine 17 by the conventional 3 steps (Scheme 4).
Scheme 2. Synthesis of the propanamide B-region analog (One-carbon elongated
C-region). Reagents and conditions: (a) pentafluorophenol, EDC, DMF, CH2Cl2; (b)
compound 8, TEA, CH2Cl2.
Br
F
Br
F
EtO
F
b
a
H
N
H
N
O
S
O
S
NH2
O
O
O
14
13
12
For the synthesis of the one-carbon elongated A-region
analogue of 21, the methyl group of commercially available 23
was converted in 3 steps to the corresponding amine 24, which
was mesylated and then hydrogenated to give 25. The carbamoyla-
tion of 25 followed by coupling with amine 4 produced 27
(Scheme 5).
F3C
H
F
HO
F
N
N
c
d
H
N
H
O
S
O
S
O
O
N
N
O
O
15
16
For the synthesis of one-carbon elongated B-region analogues of
21, the commercially available amine 28 was mesylated and its
iodo group was converted in 2 steps to the corresponding benzyl
amine 30, followed by coupling with the amine 2 to provide 31.
On the other hand, the propionic acid 9 underwent Curtius
rearrangement and subsequent addition with the amine 4 afforded
Scheme 3. Synthesis of the propanamide B-region analog (One-carbon elongated
A-region). Reagents and conditions: (a) MsCl, pyridine, 0 °C to rt, 2 h; (b) ethyl-2-
chloropropionate, NiBr2(bpy)2, Mn, TFA, DMF, 65 °C, 15 h; (c) NaOH, THF/H2O (1:1),
60 °C, 15 h; (d) compound 4, EDC, HOBt, TEA, ACN, rt, 15 h.
a
-methyl analogue of 31 (Scheme 6).
For the synthesis of the one-carbon elongated A and B-region
H2N
F
O2N
F
O2N
F
a
b
O
S
O
O
S
O
N
H
N
H
NH2
analog of 21, the bromide 13 was converted to the corresponding
nitrile 33, which was reduced and then coupled with the
trichloroacetamide 5 to provide 34 (Scheme 7).
Finally, the commercially available amine 35 was methylated in
3 steps to give 37. Similarly, the bromide 36 was substituted with a
m-tolyl group by Buchwald–Hartwig amination to give 38. The
carbamoylation of 37 and 38 followed by coupling with the amine
4 provided the adducts 39 and 40, which were reduced and then
mesylated to produce 41 and 42, the N-methyl and N-m-tolyl
analogues, respectively, of 21 (Scheme 8).
17
18
d
19
F3C
H
N
H
H
N
PhO
F
c
N
N
F
O
S
O
n
O
O
S
O
N
H
N
O
N
H
20
21 n=1
22 n=2
Scheme 4. Synthesis of the urea B-region analog. Reagents and conditions: (a)
MsCl, NaH, DMF, 0 °C ? rt, 2 h; (b) 10% Pd/C, H2, CH2Cl2; (c) phenylchloroformate,
pyridine, THF, 0 °C, 1 h; (d) compound 4 for 21, compound 8 for 22, DMAP, MeCN,
50 °C, 6 h.
The binding affinities and potencies as agonists/antagonists of
the synthesized TRPV1 ligands were assessed in vitro by a binding
competition assay with [3H]-resiniferatoxin (RTX) and by
a
functional 45Ca2+ uptake assay using human TRPV1 heterologously
expressed in Chinese hamster ovary (CHO) cells, as previously
described.21 For the agonism assay, a saturating concentration of
antagonism assay, the dose-dependent inhibition of the capsaicin
(30 nM) stimulated calcium uptake was measured. The Ki values
for antagonism take into account the competition between
capsaicin (1 lM) was used to define maximal response. For the
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J. Ann et al. / Bioorg. Med. Chem. Lett. xxx (2016) xxx–xxx
3
H2N
F
O2N
F
O2N
F
capsaicin and the antagonist. The results are summarized in
Table 1, together with the potencies of previous lead compounds
1 and 1S.
Prototype 1, identified from previous analysis of SAR, possessed
its four principal pharmacophores including methylsulfonamide in
the A region, propanamide in the B-region, and trifluoromethyl and
4-methylpiperidinyl groups in the C-region. Docking analysis with
a-c
d,e
H
N
O
NH2
S
O
24
25
23
F3C
H
N
H
H
N
PhO
F
g
N
N
F
f
H
N
O
H
N
O
O
N
O
S
hTRPV1 revealed that hydrogen bonding and a
p–p interaction
S
O
O
with Tyr511 and hydrophobic interactions with the two pockets
composed of Met514/Leu515 and Leu547/Thr550 were critical for
activity (Fig. 2).
26
27
Scheme 5. Synthesis of the urea B-region analog (One-carbon elongated A-region).
Reagents and conditions: (a) benzoyl peroxide, NBS, CCl4, reflux, 15 h; (b)
potassium phthalimide, DMF, r.t, 15 h; (c) hydrazine monohydrate, PTSA, THF,
reflux, 6 h; (d) MsCl, Pyridine, rt, 1 h; (e) 10% Pd/C, H2 gas, THF/EtOH, rt, 15 h; (f)
phenylchloroformate, pyridine, THF/CAN; (g) compound 4, DMAP, MeCN, 50 °C, 6 h.
In order to identify whether the pharmacophores in 1 are
positioned at optimal distances from one another, we investigated
the two one-carbon elongated analogues of 1, viz. 11 and 16.
Compound 11, the one-carbon elongated analogue in the C-region,
showed 7-fold and 43-fold weaker binding affinity and antagonis-
tic potency, respectively, compared to 1. Compound 16, the
one-carbon elongated analogue in the A-region, exhibited 29-fold
and 12-fold weaker binding affinity and antagonistic potency,
respectively. The results indicated that prototype 1 possessed an
optimal interval between the key pharmacophores in the
propanamide B-region series.
Next, we explored the corresponding series of urea B-region
analogues with one-carbon homologation. The urea surrogate of
1 was examined first. Surprisingly, substitution of propanamide
in 1 with the isosteric urea, providing 21, led to a dramatic
reduction in activity, with 11-fold and 67-fold decreases in binding
affinity and antagonism, respectively, compared to 1. These results
suggested that conformational restriction in the urea B-region may
affect the positions of the pharmacophores in the A- and C-region,
shifting them away from the bioactive conformation. To explore
this issue further, we examined one-carbon elongated analogues
of 21 in the respective A- and C-regions. Whereas the one-carbon
elongated analogue 22 in the C-region proved to be a partial antag-
onist, the one-carbon elongated analogue 27 in the A-region
showed a dramatic improvement in activity with Ki = 6.77 nM
and Ki(ant) = 12.5 nM, representing approximately 12-fold increases
in binding affinity and antagonistic potency compared to 21. The
binding potency of 27 is comparable to that of 1, indicating that
compound 27 as a urea B-region antagonist proved to be a novel
antagonistic template with high potency. We also examined the
homologated analogues in the urea B-region. The one-carbon
elongated analogue 31 displayed a moderate increase in potency
F
NC
F
I
F
c
a,b
H3N
O
S
O
O
S
O
N
H
N
H
NH2
30
O
29
28
d
O
S
O
H
N
F3C
O
H
N
H
N
C
F
e
N
N
F
9
O
S
O
N
R
N
H
31 R = H
32 R = Me
Scheme 6. Synthesis of the urea B-region analog (One-carbon elongated B-region).
Reagents and conditions: (a) MsCl, Pyridine, rt, 2 h; (b) Zn(CN)2, Pd(PPh3)4, DMF,
150 °C, 15 h; (c) (i) 2 M BH3ꢀSMe2, THF, reflux, 3 h, (ii) 1 M HCl, reflux, 15 h; (d)
compound 4, DBU, DMF, 80 °C, 2 h; (e) (i) DPPA, TEA, toluene, 110 °C, 1 h, (ii)
compound 4, 80 °C, 15 h.
O
S
O
F3C
N
H
H
N
H
N
NC
F
O
N
b,c
a
F
H
N
13
S
O
N
O
33
34
Scheme 7. Synthesis of the urea B-region analog (One-carbon elongated A and
B-region). Reagents and conditions: (a) Zn(CN)2, Zn, Pd2(dba)3, dppf, DMA, sealed
tube, 120 °C, 15 h; (b) 10% Pd/C, MeOH, H2 gas, rt, 15 h; (c) compound 5, DBU, DMF,
80 °C, 2 h.
compared to 21. Its a-methyl surrogate 32 showed activity compa-
rable to that of 31. However, one-carbon elongation in both the
A- and B-regions, providing 34, caused a large decline in activity.
Previous SAR study in a series of
B-region derivatives demonstrated that the
2 showed highly potent and selective antagonism of capsaicin with
a 3-fold improvement in potency over the corresponding -methyl
a
-substituted acetamide
a-m-tolyl derivative
R
HN
H2N
F
Br
F
F
d
a-c
a
derivative 1, probably due to a specific hydrophobic interaction of
NO2
NO2
NO2
the m-tolyl group with hTRPV1.20
36
35
37 R = Me
Accordingly, we explored the N-methyl urea and N-(m-tolyl)
urea B-region analogues, 41 and 42, which were nitrogen con-
geners of the a-carbon in 1 and 2. Both proved to show only weak
e
38 R = m-tolyl
F3C
F3C
R
N
R
N
H
N
H
N
N
F
N
F
binding affinity. Additionally, 42 was unusual in that it failed under
our standard assay conditions to show functional activity, either as
an antagonist or as an agonist. This failure was traced to a slow
unset of action, presumably due to slow penetration into the cells.
If the hTRPV1-expressing CHO cells were incubated with 42 for
15 min before challenge with capsaicin, then full antagonism was
observed with Ki(ant) = 2200 nM. A further enhancement in antago-
nistic potency (Ki(ant) = 860 nM) was observed if the pre-incubation
time was extended to 30 min.
f,g
O
S
O
N
O
N
O
NO2
N
H
39 R = Me
41 R = Me
42 R = m-tolyl
40 R = m-tolyl
Scheme 8. Synthesis of the urea B-region analog (N-methyl urea). Reagents and
conditions: (a) Boc2O, TEA, CH2Cl2, reflux,15 h; (b) Cs2CO3, CH3I, DMF, 40 °C, 15 h;
(c) TFA, CH2Cl2, 0 °C ? rt, 2 h; (d) m-toluidine, Pd(OAc)2, Xantphos, Cs2CO3, 1,4-
dioxane, reflux,15 h; (e) (i) pyridine, triphosgene, toluene, rt, 2 h, (ii) compound 4,
TEA, CH2Cl2, rt, 15 h; (f) 10% Pd/C, H2 gas, MeOH, rt ? 40 °C, 30 min; (g) MsCl,
pyridine, CH2Cl2, rt, 15 h.
Using our human TRPV1 (hTRPV1) model12 built based on our
rat TRPV1 (rTRPV1) model10, we performed a flexible docking
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J. Ann et al. / Bioorg. Med. Chem. Lett. xxx (2016) xxx–xxx
Table 1
In vitro activity of synthesized compounds on hTRPV1a
F3C
H
B
N
N
F
C
O
S
N
O
A
O
A
B
C
Binding affinity Ki (nM)
Agonism EC50 (nM)
Antagonism Ki(ant) (nM)
1
ANH
ANH
ANH
ACH2NH
ANH
ANH
ACH2NH
ANH
ANH
ACH2NH
ANH
CHAMe
(S)-CHAMe
CHAMe
CHAMe
NH
CH2
CH2
(CH2)2
CH2
CH2
(CH2)2
CH2
CH2
CH2
CH2
7.90
2.95
54
230
83
210
6.77
59
31.6
410
1160
490
( 1.6)
( 0.73)
( 13)
( 32)
( 27)
( 46)
( 0.48)
( 12)
( 3.4)
( 27)
( 180)
( 120)
NE
NE
NE
NE
NE
29%
NE
NE
NE
NE
NE
NE
2.22
1.26
95
( 0.47)
( 0.28)
( 26)
( 5.5)
( 50)
1S
11
16
21
22
27
31
32
34
41
42
27.6
149
49%
12.5
18.7
28.1
199
59
NH
NH
( 4.2)
( 6.1)
( 8.5)
( 50)
NHCH2A
NHCH(Me)A
NHCH2A
NHAMe
NHAPh(3-Me)
CH2
CH2
( 20)
ANH
860b
( 290)b
a
NE: no effect; values are the mean SEM of at least three experiments; where indicated, % represents the % agonism or antagonism at 3–30 lM.
Measured with 30 min pre-incubation before challenge with capsaicin; value with 15 min pre-incubation Ki(ant) = 2200 560 nM.
b
Figure 2. Docking results of 27 and 1S in the hTRPV1 model. (A) 2-D illustration of the binding interactions between 27 (left) and 1S (right) with hTRPV1. Hydrogen bonding
interactions are indicated by blue dashed line arrows and hydrophobic interactions are displayed with curved patches. (B) The Fast Connolly surface of hTRPV1 and the van
der Waals surface of 27 (left) and 1S (right). The molecular surface of hTRPV1 is created by using MOLCAD and presented with the lipophilic potential property. For clarity, the
surface of hTRPV1 is Z-clipped and that of the ligands are colored individually by magenta (27) or purple (1S).
study to investigate the binding interactions of compound 27.22
Compared with the lead compound 1S, compound 27 has a urea
group in the B-region and an additional methylene group in the
A-region. As shown in Figure 2, the binding mode of 27 was
generally similar to that of 1S.12 The urea group in the B-region
was able to form a hydrogen bond with Tyr511 and also con-
tributed to the appropriate positioning of A- and C-regions for
the hydrophobic interactions. The N-benzylmethanesulfonamide
group in the A-region occupied the deep bottom hole and formed
hydrophobic interactions with Tyr511, Tyr554, Ile564, and Ile569.
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J. Ann et al. / Bioorg. Med. Chem. Lett. xxx (2016) xxx–xxx
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The fluorine atom in the A-region made hydrogen bonds with
Lys571 and the S@O of the sulfonamide group participated in
hydrogen bonding with Ser512. The 3-trifluoromethyl group in
the C-region extended toward the hydrophobic area composed of
Leu547 and Thr550. Finally, the 4-methylpiperidine ring in the
C-region was involved in the hydrophobic interactions with
Tyr511, Met514, and Leu515.
In summary, we have investigated a series of homologated
analogues of prototype antagonist 1 and its urea B-region surro-
gate as hTRPV1 ligands. From systematic one-carbon elongation
in respective pharmacophoric regions, we identified N-(3-fluoro-
4-methylsulfonamidomethylphenyl)urea, a one-carbon elongated
analogue of the A-region in the urea B-region series, as a novel
and potent TRPV1 antagonistic template. Its representative com-
pound 27 showed high affinity and potent antagonism with
Ki = 6.77 nM and Ki(ant) = 12.5 nM which was comparable to that
of 1. Since the B-region of compound 27 is achiral urea unlike
the chiral propanamide of 1, it has more synthetic accessibility
for further optimization and development. Docking analysis of
compound 27 in our hTRPV1 homology model indicated that its
binding mode was similar with that of 1S previously reported.
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Acknowledgments
16. Ryu, H.; Seo, S.; Cho, S.-H.; Kim, M. S.; Kim, M.-Y.; Kim, H. S.; Ann, J.; Tran, P.-T.;
Hoang, V.-H.; Byun, J.; Cui, M.; Son, K.; Sharma, P. K.; Choi, S.; Blumberg, P. M.;
Frank-Foltyn, R.; Bahrenberg, G.; Koegel, B.-Y.; Christoph, T.; Frormann, S.; Lee,
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This work was supported by the Korea Science and Engineering
Foundation (KOSEF) grant funded by the Korea government
(MOST) (NRF-2014M3A9B5073755), National Leading Research
Lab (NLRL) program (2011-0028885), National Natural Science
Foundation of China (81502927), Liaoning S&T Project
(2014226032, 2015020733 and 2015001002), Hainan S&T Project
(KYYS-2014-66), and in part by the Intramural Research Program
of the NIH, Center for Cancer Research, NCI (Project Z1A BC
005270) in the USA.
References and notes
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22. The 3D structures of the ligands were generated with Concord and energy
minimized with MMFF94s force field and MMFF94 charge until the rms of
Powell gradient was 0.05 kcal molꢁ1 Aꢁ1 in SYBYL-X 2.0 (Tripos Int., St. Louis,
MO, USA). The flexible docking study on our hTRPV1 model was performed
using GOLD v.5.2 (Cambridge Crystallographic Data Centre, Cambridge, UK),
which employees a genetic algorithm (GA) and allows for full ligand flexibility
and partial protein flexibility. The binding site was defined as 8 Å around the
capsaicin complexed in the hTRPV1 model. The side chains of the nine residues
which are important for ligand binding, (i.e., Tyr511, Ser512, Met514, Leu515,
Leu518, Phe543, Leu547, Thr550, and Asn551) were allowed to be flexible with
‘crystal mode’ in GOLD. Compound 27 was docked using the GoldScore scoring
function, and the other parameters remained as default. All the computation
calculations were undertaken on an IntelÒ XeonTM Quad-core 2.5 GHz
workstation with Linux Cent OS release 5.5.
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Please cite this article in press as: Ann, J.; et al. Bioorg. Med. Chem. Lett. (2016), http://dx.doi.org/10.1016/j.bmcl.2016.06.010