Structure-based de novo design and synthesis of aminothiazole-based p38 MAP kinase inhibitors

Article abstract of DOI:10.1016/j.bmcl.2015.07.094

Abstract p38 mitogen-activated protein kinase (MAPK) is a promising target for the development of therapeutics for various immunological diseases. We designed and synthesized aminothiazole-based p38 MAPK inhibitors of with IC₅₀ values ranging from 0.1 to 2 μM by means of the structure-based de novo design of phenyl-(2-phenylamino-thiazol-5-yl)-methanone scaffold. Because these newly identified inhibitors were also screened for having desirable physicochemical properties as a drug candidate, they deserve consideration for further investigation as anti-inflammatory drugs. Structural features relevant to the stabilization of the newly identified inhibitors in the ATP-binding site of p38 MAPK are discussed in detail.

Full text of DOI:10.1016/j.bmcl.2015.07.094

Bioorganic & Medicinal Chemistry Letters 25 (2015) 3784–3787
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Structure-based de novo design and synthesis of aminothiazole-
based p38 MAP kinase inhibitors
b
b,
Hwangseo Park a, , Soyoung Lee , Sungwoo Hong
⇑
⇑
a Department of Bioscience and Biotechnology, Sejong University, Seoul 143-747, Republic of Korea
b Center for Catalytic Hydrocarbon Functionalization, Institute for Basic Science (IBS) & Department of Chemistry, Korea Advanced Institute of Science and Technology (KAIST),
Daejeon 305-701, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
p38 mitogen-activated protein kinase (MAPK) is a promising target for the development of therapeutics
for various immunological diseases. We designed and synthesized aminothiazole-based p38 MAPK inhi-
bitors of with IC50 values ranging from 0.1 to 2 lM by means of the structure-based de novo design of
phenyl-(2-phenylamino-thiazol-5-yl)-methanone scaffold. Because these newly identified inhibitors
were also screened for having desirable physicochemical properties as a drug candidate, they deserve
consideration for further investigation as anti-inflammatory drugs. Structural features relevant to the sta-
bilization of the newly identified inhibitors in the ATP-binding site of p38 MAPK are discussed in detail.
Ó 2015 Elsevier Ltd. All rights reserved.
Received 7 July 2015
Revised 28 July 2015
Accepted 31 July 2015
Available online 5 August 2015
Keywords:
De novo design
Kinase
p38 MAPK
Inhibitor
Anti-inflammatory drugs
p38 mitogen-activated protein kinase (MAPK) plays a key role
in the regulation of inflammatory processes, and is responsible
for the pathogenesis of various inflammatory diseases including
rheumatoid arthritis (RA), multiple sclerosis, and neuropathic
pain.1 Actually, a high-level expression of cyclooxygenase-2 and
interleukin-6 (IL-6) in the synovial cell of RA stems from the acti-
vation of p38 MAPK by macrophage migration inhibitory factor,
which is a key regulatory cytokine in innate and adaptive immune
responses.2 It was also demonstrated that the inhibition of p38
MAPK had the effect of decreasing the production of tumor necro-
dibenzosuberone,14 and pyrimidinylisoxazole15 moieties as a key
structural element. A rational fragment-based design approach
was also applied using structural information on p38 MAPK.16
A few years ago, we identified novel classes of p38 MAPK inhi-
bitors based on the virtual screening with docking simulations
between p38 MAPK and putative inhibitors.17 The most potent
inhibitor found in this study was (4-amino-2-phenylamino-
thiazol-5-yl)-phenylmethanone (1). We undertake a structure-
based de novo design of aminothiazole 1 as the molecular core
using the modified scoring function. Even with 3D structure of
the target protein, the results of de novo design have not always
been successful due to the imperfections in the scoring function
to compute the binding free energy between the target protein
and a putative ligand.18 This inaccuracy can be attributed in a large
part to the underestimation of ligand solvation effects in protein–
ligand binding, which leads to the overestimation of the binding
affinity of a ligand with polar moieties.19 Therefore, to enhance
the efficiency of de novo design, we modified the scoring function
by the addition of a proper solvation free energy term in the scor-
ing function. This augmentation of the scoring function makes it
possible to calculate the desolvation cost for a ligand to be bound
to the receptor protein. On the basis of the results for docking sim-
ulations with the improved scoring function, we will also address
the binding forces that are responsible for stabilization of the
newly identified inhibitors in the ATP-binding site of p38 MAPK.
sis factor-a and IL-1, which culminated in the suppression of var-
ious inflammatory diseases.3,4 Further persuasive evidence was
provided from clinical trials to support that the inhibition of p38
MAPK activity would be an effective therapeutic strategy for the
treatment of RA.2 p38 MAPK has thus served as a promising target
for the development of therapeutics for various immunological
diseases.5
Accordingly, a great deal of efforts has been devoted to the dis-
covery of p38 MAPK inhibitors. Since the discovery of a pyridinyl-
imidazole-based inhibitor,6 potent and structurally diverse p38
MAPK inhibitors have been reported including diaryl pyrazole,7
fused pyrazole,8 dibenzeno[a,d]cycloheptenone,9 N-aryl pyridi-
none,10,11 pyridopyridazin-6-one,12 methylphenylpyridazin-3-one,13
⇑
Corresponding authors. Tel.: +82 2 3408 3766, +82 42 350 2811; fax: +82 2
3408 4334, +82 42 350 2812.
3-D atomic coordinates in the X-ray crystal structure of p38
a
MAPK in complex with a potent inhibitor (PDB code: 3FMK) were
E-mail addresses: hspark@sejong.ac.kr (H. Park), hongorg@kaist.ac.kr (S. Hong).
http://dx.doi.org/10.1016/j.bmcl.2015.07.094
0960-894X/Ó 2015 Elsevier Ltd. All rights reserved.

H. Park et al. / Bioorg. Med. Chem. Lett. 25 (2015) 3784–3787
3785
used as the receptor model in the de novo design for our structure-
activity relationship (SAR) study. The structure-guided design of
new p38 MAPK inhibitors was performed in three steps. First, the
structural modifications were made to the initial p38 MAPK inhibi-
tor (1) to obtain the better scaffold from which a number of new
potent inhibitors could be derivatized. This led to the identification
structure-based de novo design with two constraints. First, we
selected only the structures similar to 1 with Tanimoto coefficient
higher than 8.0 to ensure tight binding in the ATP binding site of
p38 MAPK. The output structures were then screened further for
having the lower
with the increased binding affinity.
D
Gabq values than 1 to select the new scaffolds
of phenyl-(2-phenylamino-thiazol-5-yl)-methanone (2) as
promising scaffold for designing new p38 MAPK inhibitors.
a
Due to the two severe constraints imposed in the de novo
design, we were able to find only one structure (2) that was antic-
ipated to be a promising scaffold from which new potent p38
MAPK inhibitors could be derivatized. As can be seen in Figure 1,
it differs from 1 only in the lack of –NH2 moiety on the central thi-
azole ring. The calculated binding free energy and solvation free
In the second step, various derivatives of 2 were generated
based on the calculated binding mode of 2 in the ATP-binding site
of p38 MAPK. This started with the structural analysis of the ATP-
binding pocket using the POCKET module of the LigBuilder pro-
gram.20 The structure of p38 MAPK in complex with 2 obtained
from docking simulations with the AutoDock program21 served
as the input to find the key interaction residues in the ATP-
binding site. To generate various derivatives of 2 as the candidates
for a potent inhibitor, the proper chemical moieties at the substitu-
tion positions were selected with the genetic algorithm. To score
and rank the generated derivatives, we used the empirical scoring
function suggested by Wang et al. that included van der Waals,
hydrogen bond, electrostatic, and entropic terms.22 To reduce the
computational burden, only the generated derivatives that could
satisfy the bioavailability rules as a drug candidate23 were selected
for further analysis. Based on the filtration criteria, we obtained
2259 derivatives that were estimated to have higher inhibitory
activity against p38 MAPK than 2.
Although the effects of ligand solvation have been shown to be
critically important in protein–ligand association,19 the current
scoring function of the LigBuilder program lacks a solvation term.
In the third step of de novo design, therefore, the derivatives of 2
generated with LigBuilder were further screened with a new bind-
ing free energy function constructed by combining an appropriate
solvation free energy term to the original scoring function of the
AutoDock program. This modified scoring function can be
expressed as follows:24
energy (
of 1. Keeping it in mind that the binding free energy of a protein–
ligand complex in aqueous solution (
Gabq) can be approximated as
the difference between that in the gas phase (
Gbgas) and the Gsol
value of ligand, we computed the two energy components sepa-
rately to estimate their relative contributions to
Gabq. Judging from
the lower
Ggbas value of 1 than 2, the former seems to bind more
DG
sol) of 2 are shown in Table 1 in comparison with those
D
D
D
D
D
tightly in the ATP-binding site of p38 MAPK than the latter.
However, the biochemical potency of 1 seems to be limited by
the relatively high desolvation cost (ꢀ
DG
sol) for binding to p38
MAPK. As a consequence, 1 and 2 are predicted to be almost
equally potent p38 MAPK inhibitors. This result exemplifies the
necessity of the solvation free energy term in the scoring function
to estimate the relative inhibitory activities. The significant contri-
bution of D D
Gsol to Gabq also indicates that in order to enhance the
potency of a p38 MAPK inhibitor with structural modifications, the
resulting increase in the strength of enzyme-inhibitor interactions
should be sufficient to surmount the increased stabilization in
aqueous solution. In the de novo design to find new potent p38
MAPK inhibitors, we selected 2 as the molecular core instead of 1
because the former had the more chance for derivatization than
the latter due to the structural simplicity.
Using the binding free energy function in Eq. 1, the derivatives
of 2 generated with LigBuilder were rescored according to the
binding affinity in the ATP-binding site of p38 MAPK. Top-ranked
derivatives (100 compounds) were then selected as virtual hits,
which were inspected for synthetic availabilities. Finally, twenty
derivatives of 2 were synthesized and tested for inhibitory activity
against p38 MAPK.27 The general synthetic route for the prepara-
tion of substituted aminothiazole derivatives is shown in
Scheme 1.
!
XX
Aij Bij
D
Gabq ¼ W
12 ꢀ
v
dW
rij
r6ij
i¼1 j¼1
!
XX
XX
qiqj
j¼1 eðrijÞrij
Cij Dij
þ Whbond
EðtÞ 12 ꢀ
þ Welec
10
ij
rij
r
i¼1 j¼1
i¼1
!
2
r
X
X
ij
2
2
r
þ WtorNtor
þ
Si Omi ax
ꢀ
Vjeꢀ
ð1Þ
i¼1
j–i
To address the possibility of tight binding of 2 in the ATP-
binding site, we carried out docking simulations between p38
MAPK and 2 using the modified scoring function shown in Eq. 1.
In the calculation of the molecular solvation free energies of the
derivatives of 2, we used the atomic parameters developed by Park
because they proved to be useful for estimating the solvation free
energies of various organic molecules in SAMPL4 blind prediction
challenge.25 This modification of the scoring function seems to
have an effect of raising the probability of finding the actual p38
MAPK inhibitors because the overestimation of the binding affinity
of a polar group can be avoided effectively. Indeed, the superiority
of this modified scoring function to the previous one was well-
appreciated in recent studies for virtual screening of kinase
inhibitors.26
Although 1 is a submicromolar p38 MAPK inhibitor, it seems to
be a poor molecular core to serve as a starting point of drug discov-
ery due to the presence of an amino moiety on the central thiazole
ring. This functional group is actually responsible for high desolva-
tion cost by facilitating the formation of multiple hydrogen bonds
with water molecules,25 which would have the effect of limiting
the inhibitory activity of a candidate inhibitor derived from 1.
Therefore, we decided to make some structural modifications of
1 to obtain the better inhibitor scaffold than 1 with similar
biochemical potency. This could be made possible by the
R2
O
O
R1
S
N
S
N
NH
NH
H2N
H
1
2
Figure 1. Structural modifications of 1 to find the better inhibitor scaffold for de
novo design.
Table 1
Calculated
energy value is given in kcal/mol
D , DG D
Ggbas sol, and Gabq values of 2 in comparison with those of 1. Each
Scaffold
D
Ggbas
D
Gsol
D
Gabq
1
2
ꢀ24.8
ꢀ21.4
ꢀ13.7
ꢀ10.1
ꢀ11.1
ꢀ11.3

3786
H. Park et al. / Bioorg. Med. Chem. Lett. 25 (2015) 3784–3787
Table 2
R2
O
O
R1
Structures and inhibitory activities of the derivatives of 2 together with the calculated
binding free energies (
R1
S
N
a
b
D
Gabq) in kcal/mol
S
N
S
N
Cl
Cl
NH
R3
R1
O
Scheme 1. Reagents and conditions (a) (i) nBuLi, THF, ꢀ60 °C, 1 h. (ii) Substituted
benzonitrile, THF, ꢀ30 °C, 17 h. (iii) AcOH ꢀ30 °C, 8 h; (b) substituted aniline, 4 N
R4
R2
S
N
NH R5
HCl in 1,4-dioxane, MeOH, lW 120 °C.
R1
R2
R3
R4
R5
D
Gbaq
IC50 (lM)
Figure 2 shows the calculated binding mode of 2 in comparison
with that of 1. Both 1 and 2 appear to be stabilized in the ATP-
binding site due in part to the establishment of a hydrogen bond
between their anilinic moiety and the side-chain carboxylate ion
of Glu71. It is also a common feature in the calculated binding
modes of 1 and 2 that the two terminal phenyl rings occupy the
hydrophobic regions of the ATP-binding pocket through van der
Waals interactions with the nonpolar side chains including
Val38, Ala51, Leu75, Ile84, Leu104, Met109, Ala157, Leu167, and
Phe169. However, the binding mode of 1 differs from that of 2 in
that the –NH2 moiety attached to central thiazole ring donates
Compd
2
H
H
H
H
H
H
H
H
H
H
H
H
OCH3
OH
H
H
H
H
F
OH
F
H
H
H
Cl
Br
H
H
H
H
OCH3
H
H
OH
H
H
H
H
H
H
H
NH2
H
H
H
H
H
–NHCOC6H5
H
H
H
NO2
–NHCOC6H5
H
H
F
F
H
F
H
F
H
H
H
H
H
H
H
H
F
H
F
H
H
H
ꢀ13.4
ꢀ14.9
ꢀ14.7
ꢀ14.7
ꢀ14.6
ꢀ14.6
ꢀ14.6
ꢀ14.4
ꢀ14.4
ꢀ14.3
ꢀ14.2
ꢀ14.2
ꢀ14.1
ꢀ14.0
ꢀ14.0
ꢀ13.9
ꢀ13.8
ꢀ13.8
ꢀ13.7
ꢀ13.7
ꢀ13.6
1.07
0.18
0.25
0.33
0.45
0.61
0.79
0.91
0.94
1.07
1.20
1.23
1.31
1.44
1.62
1.98
2.04
12.7
16.2
116
2a
2b
2c
2d
2e
2f
2g
2h
2i
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Br
Cl
H
2j
2k
2l
two hydrogen bonds in
a bidentate form to the backbone
H
2m
2n
2o
2p
2q
2r
2s
2t
Cl
Cl
Cl
Cl
Cl
Cl
CH3
Cl
aminocarbonyl oxygens of Ala51 and Leu104. The establishment
of these two hydrogen bonds can be invoked to explain the lower
D
Ggbas value of 1 than 2 (Table 1). However, it seems to be difficult
H
H
H
H
for 1 to serve as a good molecular core in the de novo design
because the conformational change by the addition of chemical
groups may lead to weakening of the hydrogen bond interactions.
Because 2 has the similar binding free energy to 1 even with rela-
tively weak interactions with p38 MAPK, we choose 2 as the start-
ing point to design new p38 MAPK inhibitor. Many potent
inhibitors are likely to be identified by introducing various chem-
ical moieties at the two terminal phenyl rings of 2 because they
reside distant from the protein atoms.
Table 2 lists the structures and IC50 values of these finally
selected molecules. We note that eight derivatives of 2 have high
inhibitory activities with respect to p38 MAPK at submicromolar
level. Because all the derivatives in Table 2 but 2s contain the polar
moieties only, hydrogen-bond and dipole–dipole interactions seem
to be the more significant binding forces than hydrophobic interac-
tions to stabilize the derivatives of 2 in the ATP-binding site of p38
MAPK. It is also noteworthy that most derivatives with high bio-
chemical potency possess a chlorine atom at R1 position. The
NO2
NH2
H
H
NH2
H
>200
substitution of a methyl group (2s) for Cl at R1 (2e) appear to result
in the decrease of inhibitory activity to a dramatic extent, which
indicates the necessity of the chlorine atom to form a stable p38
MAPK-inhibitor complex. The most potent inhibitor (2a) was gen-
erated when the two fluorine atoms were introduced at R3 and R5
positions in addition to chlorine at R1. Although small substituents
appear to be preferred at most substitution positions, a few micro-
molar inhibitors (2j and 2o) are obtained with the benzamide moi-
ety at R4 position. Because all the inhibitors shown in Table 2 were
also screened for having the desirable physicochemical properties
as a drug candidate, they deserve consideration for further investi-
gation to develop anti-inflammatory drugs.
To obtain energetic and structural insight into the inhibitory
activity of the newly identified p38 MAPK inhibitors, their binding
modes in the ATP-binding site were investigated using the modi-
fied AutoDock scoring function. Figure 3 shows the calculated
Figure 2. Calculated binding modes of 1 and 2 in the ATP-binding site of p38 MAPK.
Carbon atoms of p38 MAPK, 1, and 2 are indicated in cyan, green, and pink,
respectively. Hydrogen bonds are indicated with dotted lines.
Figure 3. Calculated binding mode of 2a in the ATP-binding site of p38 MAPK.
Carbon atoms of the protein and the ligand are indicated in cyan and green,
respectively. Each dotted line indicates a hydrogen bond.

H. Park et al. / Bioorg. Med. Chem. Lett. 25 (2015) 3784–3787
3787
5. Fischer, S.; Koeberle, S. C.; Laufer, S. A. Expert Opin. Ther. Pat. 1843, 2011, 21.
binding mode of 2a. It is noted that the two fluorine atoms on one
terminal phenyl ring and the –NH– moiety connecting the phenyl
and thiazole rings of 2a establish three hydrogen bonds with the
backbone amidic groups of Met109, Asp112, and His107. These
three hydrogen bonds seem to play a role of anchor in binding of
the inhibitor to p38 MAPK because residues 107–112 are located
at the entrance of the ATP-binding site. This structural feature is
consistent with the previous X-ray crystallographic studies on
p38 MAPK-inhibitor interactions in which the formation of multi-
ple hydrogen bonds with the backbone groups in the ATP-binding
site was shown to be necessary for high biochemical potency.28
The chlorine atoms on the other terminal phenyl ring of 2a appears
to be accommodated in the hydrophobic pocket comprising the
side chains of Leu75, Ile84, and Leu167, which should also be a sig-
nificant binding force to stabilize the p38 MAPK-2a complex. The
inhibitor 2a can be further stabilized in the ATP-binding site
through the hydrophobic interactions of its aromatic rings with
the nonpolar side chains of Val30, Val38, Ala51, Leu75, Ile84,
Leu104, Ala157, and Leu167. Judging from the structural features
of the calculated p38 MAPK-2a complex, the submicromolar inhi-
bitory activity of 2a can be attributed to the multiple hydrogen
bonds and the hydrophobic interactions established simultane-
ously in the ATP-binding site. It is also worth noting that the num-
ber of hydrogen bonds increases from one in p38 MAPK-2 (Fig. 2)
to three in p38 MAPK-2a complex (Fig. 3), which would have the
effect of increasing the binding affinity. Because the hydrophobic
interactions are established in similar way in the two p38 MAPK-
inhibitor complexes, the strengthening of the hydrogen-bond
interactions can be invoked to explain the ten-fold higher inhibi-
tory activity of 2a than 2.
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In summary, we have identified 17 inhibitors of p38 MAPK with
biochemical potency at submicromolar and low micromolar levels
by means of the structure-based de novo design using the phenyl-
(2-phenylamino-thiazol-5-yl)-methanone scaffold. Besides the
good inhibitory activities, these inhibitors were also screened for
having desirable physicochemical properties as a drug candidate.
Detailed binding mode analyses with docking simulations indicate
that the inhibitors would be stabilized in the ATP-binding site of
p38 MAPK by the simultaneous establishment of multiple hydro-
gen bonds and van der Waals interactions.
23. Lipinski, C. A.; Lombardo, F.; Dominy, B. W.; Feeney, P. J. Adv. Drug. Delivery Rev.
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24. WvdW, Whbond, Welec, and Wtor are the weighting factors of van der Waals,
hydrogen bond, electrostatic interaction, and torsional term, respectively. rij
represents the interatomic distance, and Aij, Bij, Cij, and Dij are related to the
depths of the potential energy well and the equilibrium separations between
the protein and ligand atoms. The hydrogen-bond term has an additional
Acknowledgments
weighting factor, E(t), representing the angle-dependent directionality.
A
sigmoidal function ( (rij)) proposed by Mehler et al. was used as the distance-
e
dependent dielectric constant to compute the electrostatic interactions
between p38 MAPK and ligand atoms. In the entropic term, Ntor is the
number of rotatable bonds in the ligand. In the desolvation term, Si and Vi are
the solvation parameter and the fragmental volume of atom i, respectively,
while Oimax stands for the maximum atomic occupancy Mehler, E. L.; Solmajer,
T. Protein Eng. 1991, 4, 903.
This research was supported by National Research Foundation
of Korea (NRF) funded by Ministry of Education, Science and
Technology (NRF-2011-0022858) and Institute for Basic Science
(IBS-R010-G1).
25. Park, H. J. Comput. Aided Mol. Des. 2014, 28, 175.
26. (a) Park, H.; Shin, Y.; Choe, H.; Hong, S. J. Am. Chem. Soc. 2015, 137, 27; (b) Park,
H.; Eom, J.-W.; Kim, Y.-H. J. Chem. Inf. Model. 2014, 54, 2139; (c) Park, H.; Hong,
S.; Kim, J.; Hong, S. J. Am. Chem. Soc. 2013, 135, 8227.
27. The IC50 determinations were performed at the Reaction Biology Corp
(Malvern, PA, USA).
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