Study Quantitative Structure Relationship And Activity 3D Antikanker Of

Derivative Compounds 4- (Pyridine-3-yl) Phenol As Inhibitors P90 Ribosomal

S6 Kinase

Abstract p90 Ribosomal S6 Kinase (RSK) have emerged as attractive targets for the
design of anticancer drugs. 3D-QSAR (comparative molecular field analysis
(CoMFA) and comparative molecular similarity indices analysis (CoMSIA)) studies
were performed on a series of 4- (pyridine-3-yl) phenol as RSK inhibitors. The
CoMFA and CoMSIA models using 16 compound inhibitors in the training set gave
Q2 values of 0.597 and 0.563,and R2 values of 0.993 and 0.990, respectively. The
adapted alignment method with the suitable parameters resulted in reliable models.
The contour maps produced by the CoMFA and CoMSIA models were employed to
rationalize the key structural requirements responsible for the activity. Based on the
3D-QSAR and docking results, a set of new molecules with high predicted activities
were designed.

Keywords: 3D-QSAR; CoMFA; CoMSIA; 4- (pyridine-3-yl); p90 Ribosomal S6

Kinase (RSK)

1. Introduction
p90 ribosomal S6 kinase is initially referred to as ribosomal S6 kinase
(S6K). The identification of two kinase protein kinases 85-90 kDa (S6KI and
S6KII) with biochemical purification causes cloning of cDNA to encode
homologous proteins which are then renamed p90 ribosomal S6 kinase. The
family of RSK proteins comprises a much needed serine/ trionin kinase group
downstream of the Ras-MAPK line and regulates various cellular processes such
as cell growth and motility, cell proliferation and cellular viability [1]. RSK
kinases have an unusual structure in which an N-terminal kinase responsible for
the phosphorylation of RSK’s described substrates is fused to a C-terminal kinase
that seems to be dedicated to activating the N-terminal RSK kinase. The current
understanding of the activation scheme suggests that ERK (MAPK)
phosphorylates and activates the C-terminal kinase, which then creates a
phosphorylated docking site for PDK1 to bind to and activate the N-terminal
kinase. This activation scheme has been accepted as canonical, but additional
activating phosphorylation events have been described and may transfer the strict
control of RSK activity from the MAP kinase signaling pathway to other
signaling pathways [2,3].
 A Pyridine series of 4- (pyridine-3-yl) phenol with RSK inhibitory
activities were reported. These 4- (pyridine-3-yl) phenol, with excellent RSK
inhibitory activities. [4]. In the present study, three-dimensional quantitative
structure-activity relationship (3D-QSAR) methods along with used to explore the
structure-activity relationship (SAR) of these 4- (pyridine-3-yl) phenol. 3D-
QSAR methods, comparative molecular field analysis (CoMFA) and comparative
molecular similarity indices analysis (CoMSIA), were performed to foresee the
activities of these 4- (pyridine-3-yl) phenol and offered the regions where
interactive fields (steric, electrostatic, hydrophobic, hydrogen bond donor and
hydrogen bond acceptor fields) may increase or decrease the activity. These
developed models can help understanding the SAR of 4- (pyridine-3-yl) phenol
and can also serve as a valuable guide for the design of novel inhibitors with
robust potency. Furthermore, we have designed a number of new 4- (pyridine-3-
yl) phenol derivatives by utilizing the structure information obtained from the
CoMFA and CoMSIA models, which exhibit excellent predictive potencies.
Moreover, the predicted activities of these newly designed molecules may be
reliable.

2. Materials and Methods

2.1 Data Sets
All Pyridine Series of the 21 compounds and associated data involved in
this study were obtained from literature [4]. The inhibitory activity data were
reported as IC50 against RSK. The IC50 values were converted into pIC50
according to the formula in Equation 1 [5]. In CoMFA and CoMSIA models, the
dataset was randomly divided into training and test sets including 16 and 5
molecules, respectively. The structures of the molecules are shown in Table 1 and
associated inhibitory activities are shown in Table 2, where pIC50 values for 21
inhibitors ranged from 5.3188 to 8.574.

pIC50 = −Log IC50

OH
R1 R1

R2

N
 Table 1. The structures of the training and test set molecules.

Subtituen IC50 pIC50

Senyawa Rumus Struktur
(nM) (nM)
R1 R2
OH
OH
OH
1* H 0.18 6.7447

N
OH
F F
OH
OH
2 F 0.050 7.301

N
OH
F F

3 F 0.060 7.2218
N
OH
F F
O
4* F O 0.13 6.8861

N
OH
F F
NH
5 F NH 2.1 5.6778
N
OH
F F

6 F 0.78 6.1079
N
OH
F F

7* F 0.032 7.4948
N
OH
F F

8 F 0.046 7.3372
O O
N
OH
F F

9 F NH2 0.004 8.3979

O NH2
O
N
 OH
F F

10 F N 0.005 8.301
N
H N
N NH
OH
F F

11* F N 0.018 7.7447

O
N
N O
OH
F F
N
12 F N
0.004 8.3979
N
N N
OH
F F F
F
13 F 0.094 7.0269
N
OH
F F

14 F 0.007 8.1549
N
OH
F F
O
O
15 F 0.008 8.0969
N
O OH
F F
O
N
16* F H N
H
0.020 7.699
N
OH
F F
NH NH
N N
17 F 0.006 8.2218
N
OH
N F F
N
N
N
18 F 0.005 8.301
N
OH
O F F
O
N
N
19 F 0.004 8.3979

N
O OH
F F
O
20 F N 0.080 7.0969
N
N
 OH
F Cl Cl
F
21 Cl 4.8 5.3188

Table 2. The actual pIC50s, predicted pIC50s (Pred.) and their residuals (Res.) of the
training and test set molecules.
pIC50 Prediksi (µM)
Senyawa pIC50 (µM)
CoMFA Residual CoMSIA Residual
1* 6.7447 6.758 -0.0133 6.7422 0.0025
2 7.301 7.3982 -0.0972 7.2862 0.0148
3 7.2218 7.3126 -0.0908 7.4977 -0.2759
4* 6.8861 6.8864 -0.0003 6.9013 -0.0152
5 5.6778 5.7053 -0.0275 5.6856 -0.0078
6 6.1079 6.083 0.0249 6.0665 0.0414
7* 7.4948 7.457 0.0378 7.4699 0.0249
8 7.3372 7.2449 0.0923 7.406 -0.0688
9 8.3979 8.3551 0.0428 8.3535 0.0444
10 8.301 8.3043 -0.0033 8.3818 -0.0808
11* 7.7447 7.784 -0.0393 7.7836 -0.0389
12 8.3979 8.4429 -0.045 8.3292 0.0687
13 7.0269 6.7808 0.2461 6.9942 0.0327
14 8.1549 8.1679 -0.013 7.9425 0.2124
15 8.0969 8.0884 0.0085 8.1118 -0.0149
16* 7.699 7.684 0.015 7.6723 0.0267
17 8.2218 8.2688 -0.047 8.1833 0.0385
18 8.301 8.2658 0.0352 8.3686 -0.0676
19 8.3979 8.393 0.0049 8.3812 0.0167
20 7.0969 7.1539 -0.057 7.0584 0.0385
21 5.3188 5.3931 -0.0743 5.3114 0.0074
Test set molecules.

2.2 Molecular Modeling and Database Alignment

Molecular modeling and database alignment were performed by using the
molecular modeling package SYBYL 2.1 Tripos, Inc. [6]. The three-dimensional
structures all Pyridine Series of 4- (pyridine-3-yl) phenol were constructed by
using the Sketch Molecule module. Energy minimization of each structure was
performed using the SYBYL energy minimizer Tripos force field and Gasteiger-
Hückel charge. The maximum iterations for the minimization was set to 1000.
The minimization was terminated when the energy gradient convergence criterion
of 0.005 kcal/mol·Å was reached [7].

Figure 1. Common substructure used for alignment.

OH

Figure 2. Alignment of the compounds used in the training set.

Molecular alignment was considered as one of the most sensitive

parameters in 3D-QSAR analyses [8]. The quality and the predictive ability of the
model are directly dependent on the alignment rule [9]. In this paper, all of the
structures were aligned into a lattice box by fitting 4- (pyridine-3-yl) phenol
(Figure 1) as a common structure using compound 18 as a template, which was
the most active compound. The aligned molecules are shown in Figure 2.

2.3 CoMFA and CoMSIA Setup

CoMFA is a widely used 3D-QSAR method, which relates the biological
activity of a series of molecules with their steric and electrostatic fields. The
CoMFA descriptor fields were calculated at each lattice with a grid spacing of 1
Å and extending to 4 Å units in all three dimensions within the defined region
[10]. The Van Der Waals potentials and Coulombic terms, which represent steric
and electrostatic fields, respectively, were calculated by using the standard Tripos
force field. In the CoMFA method, a sp3 hybridized carbon atom with a charge of
1e was used as a probe atom, the energy values of the steric and electrostatic
fields were truncated at 30 kcal/mol [11].
The steric, electrostatic, hydrophobic, hydrogen bond donor and hydrogen
bond acceptor CoMSIA potential fields were calculated at each lattice intersection
of a regularly spaced grid of 1 Å and extending to 4 Å using a probe atom with
radius 1.0 Å, +1.0 charge, and hydrophobic and hydrogen bond properties of +1.
The attenuation factor was set to the default value of 0.3 [12].

2.4 Regression Analysis and Models Validation

The partial least-squares (PLS) approach, an extension of multiple
regression analysis, was applied to linearly correlate the CoMFA and CoMSIA
fields to the pIC50 values. CoMFA and CoMSIA descriptors were used as the
independent variables. Column filtering was used at the default value of 2.0
kcal/mol in the cross-validation part. The cross-validation analysis was performed
using the leave-one-out (LOO) method in which one molecule was omitted from
the dataset. The activity of the omitted molecule was then predicted by using the
model derived from the rest of the dataset [13]. The leave-one-out (LOO) cross-
validation method could check the predictivity of the obtained model and identify
the optimum number of components (ONC). Thus, the optimum number of
components (ONC) was the number of components that led to the highest cross-
validated correlated correlation coefficient r2 (r2 cv) [14]. Finally, the CoMFA
and CoMSIA models were generated using non-cross-validated PLS analysis with
the optimum number of components (ONC) determined by the cross-validation.

2.5. Predictive Correlation Co-efficient (r2pred)

The predictive abilities of 3D-QSAR models were validated by predicting
the activities of a test set of 5 compounds that were not included in the training
set. These molecules were aligned to the template and their pIC50 values were
predicted by the produced models which were obtained using the training set. The
predictive correlation coefficient (r2pred), based on the molecules of the test set, was
calculated using Equation (2):

(r2pred)= (SD-PRESS)/SD

In this equation, SD is the sum of the squared deviations between the inhibitory
activities of the test set and the mean activity of the training molecules and
PRESS is the sum of squared deviations between predicted and actual activity
values for each molecule in the test set [15]
3. Results and Discussion
3.1 CoMFA and CoMSIA Models
The statistical parameters for the CoMFA and CoMSIA models are given
in Table 3. For the CoMFA model, partial least squares (PLS) regression
produced a excellent cross-validated correlation coefficient (Q2) of 0.597 (>0.5)
with an optimized component of 6, which suggesting that the model is reliable
and it should be a useful tool for predicting the IC50 values. The non cross-
validated PLS analysis gave a high correlation coefficient (R2) of 0.993, F value
of 221.414 and a low standard error estimate (SEE) of 0.108. The contributions of
steric and electrostatic fields to this model were 0.513 and 0.487, respectively.
The external validation correlation coefficient (r2pred) value based on molecules of
the test set was 0.996 for the CoMFA model. The actual and predicted pIC50
values of the training set and test set by the model are given in Table 2. The
relationship between actual and predicted pIC50 of the training set and test set
compounds of the CoMFA model is illustrated in Figure 3a, where almost all
points are located on the diagonal line.

Table 3. Results of CoMFA and CoMSIA models.

Parameter statistik CoMFA CoMSIA

Q 2 0,597 0.563
R2 0,993 0,990
r2pred 0,996 0,996
F 221.414 153.383
SEE 0.108 0.129
N 6 3
Fraction CoMFA CoMSIA
Steric 0.513 0.162
Electrostatic 0.487 0.343
Hidrofobic - 0.170
H-Bond Donor - 0.228
H-Bond Akseptor - 0.096
Q : Cross-validated correlation coefficient. N: Optimum number of components. R2:
2

Non-cross-validated correlation coefficient. r2pred: Predictive correlation coefficient.

SEE:Standard error of the estimate. F: F -test value

Figure 3. Graph of actual versus predicted pIC50 of the training set and the test set
using CoMFA (a) and CoMSIA (b).
 ♦ Training (a) ♦ Training (b)
♦ Test 9 ♦ Test
9
8.5 8.5
8
Predicted pIC50 CoMFA

Predicted pIC50 CoMSIA

7.5 7.5
7 7
6.5 6.5
6
6
5.5
5.5
5
5 5.5 6 6.5 7 7.5 8 8.5 9 5
Actual pIC50 5 5.5 6 6.5 7 7.5 8 8.5 9
Actual pIC50

For the CoMSIA model, the statistical parameters revealed that steric,
electrostatic, hydrophobic, hydrogen bond donor and acceptor features
significantly influence the activity of the inhibitors. The CoMSIA model gave a
cross-validated correlation coefficient (Q2) of 0.563 (>0.5) with an optimized
component of 3, which suggested that the model is reliable and should be a useful
tool for predicting the IC50 values. The non cross-validated PLS analysis gave a
high correlation coefficient (R2) of 0.99, F value of 153.383 and a low error
estimate (SEE) of 0.129. The contributions of steric, electrostatic, hydrophobic,
hydrogen bond donor and acceptor fields were 0.162, 0.343, 0.170, 0.228 and
0.096, respectively. The predictive correlation coefficient (r2pred) value based on
molecules of the test set was 0.996 for the CoMSIA model. The actual and
predicted pIC50 values and residual values for training set and test set compounds
are given in Table 2. The graph of actual activity versus predicted pIC50 of the
training set and test set is illustrated in Figure 3b, where almost all points are
located on the diagonal line.

3.2. CoMFA and CoMSIA Contour Maps

The results of the CoMFA and CoMSIA models were visualized through
contour maps. These maps showed regions in 3D space where variation in
specific molecular properties increased or decreased the activity. The molecular
fields around the most active compound 20 are displayed in Figures 4–6,
accordingly. These contour maps are significant for drug design, as they showed
regions in 3D space where modifications of the molecular fields strongly
correlated with concomitant changes in biological activity.
The steric contour map of CoMFA is shown in Figure 4a, which was
almost the same as the corresponding CoMSIA steric contour map (Figure 4b).
Compound 18 was selected as a reference molecule. The steric field was
represented by green and yellow contours, in which green contours indicate
regions where presence of bulky steric groups was favored and should enhance
inhibitory activity of molecules, while the yellow contours represent regions
where occupancy of steric groups was unfavorable. As shown in Figure 4, the
presence of the green contour around the R1 position suggested that a bulky
group at this region would be favorable. For CoMFA, The yellow contour near
the position of R1 indicates that the addition of a large subtituen will decrease its
potential. While the green area around the position of R2 indicates, large
subtituents are favored and allow increased activity in the area. The yellow and
green contours can explain very well why the compounds: 7 (R1 = F and R2 =
toluene) have a much lower (0.032 μM) activity and IC50 (R1 = F and R2 = 1-
methoxy-3 -methylbenzene) (0.046 μM) compared with the compound 18 (R1 = F
and R2 = 1-methyl-4-p-tolylpiperazine) having IC50 (0.005 μM) and compound
19 (R1 = F and R2 = 4-p- tolylmorpholine) which has an IC50 value (0.004 μM).
For CoMSIA, As in the previous case, large green contours were found by the
substituent group of R2 in compound 18 (Fig. 4b), to show that large substituents
are preferred in this area compared to compounds 1-8, 11, and 20-21.
(a) (b)

Figure 4. Contour maps of CoMFA (a) and CoMSIA (b) analysis in

combination with compound 18. Steric fields: green contours (80%
contribution) indicate regions where bulky groups increase activity,
while yellow contours (20% contribution) indicate regions where
bulky groups decrease activity. Compound 18 is depicted in ball and
stick representation, colored by atom type (white C, blue N, red O,
cyan H).

The electrostatic field contour maps of CoMFA and CoMSIA are shown
in Figure 5a and b, respectively. Compound 18 was selected as a reference
molecule again. The electrostatic field is indicated by blue and red contours,
which demonstrate the regions where electron-donating group and electron-
withdrawing group would be favorable, respectively. For CoMFA, the blue
contours near the position of R2 show that subtituents with electropositive
charges can increase activity. This explains why the compounds 1 (R2 = p-
cresol), 2 (R2 = p-cresol), and 3 (R2 = toluene) with IC50 values respectively
(0.018 μM), (0.050 μM), and (0.060 μM) has a lower activity than the compound
18 (R2=1-methyl-4-p-tolylpiperazine) having greater electropositive properties
with IC50 (0.005 μM) activity and the compound 19 (R1=F and R2=4-p-
tolylmorpholine) which has an IC50 value (0.004 μM). For CoMSIA, Blue
contours show subtituents with this electropositive charge will increase activity
and red contours show subtituents with electronegative charges will increase
activity. This may explain that compound 18 has better activity than compounds
1-8, 11, and 20-21.

(a) (b)

Figure 5. Contour maps of CoMFA (a) and CoMSIA (b) analysis in

combination with compound 18. Electrostatic fields: blue contours
(80% contribution) represent regions where electron-donating groups
increase activity, while red contours (20% contribution) represent
regions where electron-withdrawing groups increase activity.
Compound 18 is depicted in ball and stick representation, colored by
atom type (white C, blue N, red O, cyan H).

CoMSIA analysis on the yellow contour hydrophobic field shows areas

where the hydrophobic properties are favorable, whereas white contours indicate
areas of preferred hydrophilic properties. This suggests that adding hydrophobic
substituents in the R2 region of benzene and cyclohexane structure of compound
18 may help increase activity. Whereas if adding hydrophilic subtituents in the R2
region around cyclohexan may help increase the activity as in Figure 6a.

(a) (b)

(c)
 Figure 6. Contour maps of CoMSIA analysis in combination with
compound 18. Hydrophobic fields (a), the yellow and white contours
(80% and 20% contributions) indicate favorable and unfavorable
hydrophobic groups; Hydrogen bond donor contour map (b), the cyan
and purple contours (80% and 20% contributions) indicate favorable
and unfavorable hydrogen bond donor groups; Hydrogen bond
acceptor contour map (c), the magenta and red contours (80% and
20% contributions) indicate favorable and unfavorable hydrogen bond
acceptor groups. Compound 18 is depicted in ball and stick
representation, colored by atom type (white C, blue N, red O, cyan H).

CoMSIA analysis on the magenta contour bond acceptor area around the
benzene R2 substituent of the hydrogen bond acceptor indicates a potential
increase in activity while the red contour indicates a potential decrease in activity
as in Figure 6b. CoMSIA analysis on the hydrogen contour hydrogen donor donor
field around the OH substituent of the hydrogen bond donor has the potential to
increase activity while the purple contour area indicates the hydrogen bond donor
substituent decreases the activity as shown in compound 18 in figure 6c.

3.3 Design for New Molecules

The detailed contour map analysis of both COMFA and CoMSIA models
and the docking analysis empowered us to identify structural requirements for the
observed inhibitory activity (Figure 7). In detail, bulky, electron-donating,
hydrophobic, and hydrogen bond acceptor substituents at the terminal of R2 (e.g.,
cyclohexane) would increase activity. Moreover, the electron-donating chain (-
CH2CH2-) in area cyclohexane and R2 may be essential for the activity of the
inhibitors. Based on the current 3D-QSAR model-activity-activity relationship,
the contour maps analysis from CoMFA and CoMSIA has provided details of
which parts can be substituted from the parent compound to increase activity. In
detail, bulky, electropositive, hydrophobic, and hydrogen bonding compounds
which, when added substituents in the R2 region (eg, cyclohexane) have increased
activity. Electronegative, hydrophilic, and hydrogen bond acceptor substances
which, if added subtituents in the region of R2 (eg, benzene) will show the
potential for increased activity. A series of new compounds have been designed
and to be predicted (table 4), with molecule 18, one of the most active compounds
used as a parent compound. A set of 30 new compounds is used as the prediction
design of the highest activity of new compounds. From the results of the study
there are several new compound designs that have higher predictive value of both
PIC50 CoMFA and pIC50 CoMSIA than compound 18 is HA3-HA7, HA9-
HA10, HA22-HA23, HA25, HA27, and HA29. The comparison of the predicted
values of pIC50 CoMFA and pIC50 CoMSIA new compound design versus
compound 18 can be seen in the graph of figure 8.

Table 4. Structure, predicted pIC50 values, and surflex-dock total score of the
newly designed molecules.

OH
F F
N
N R2
R1

SUBTITUEN pIC50 Total

NO COMPOUND R1 R2 CoMFA CoMSIA Score
1 18 H H 8.2852 8.3711 7.8946
2 HA1 H Br 8.2739 8.4695 8.0971
3 HA2 Cl Br 8.1264 8.4769 8.0568
4 HA3 H CH2CH2C(CH3)3 8.367 8.4849 8.9052
5 HA4 H CH3 8.2898 8.4054 8.3943
6 HA5 CH3 CH3 8.3287 8.4293 8.4658
7 HA6 CH3 Cyclohexane 8.4222 8.4423 9.3331
8 HA7 CH3 CH2CH3 8.3794 8.4128 9.6933
9 HA8 Cl Cl 8.0657 8.495 8.1035
10 HA9 CH2CH2CH3 CH2CH2CH3 8.4431 8.4599 8.3137
11 HA10 H OH 8.3611 8.436 8.3429
12 HA11 H OCF3 8.2087 8.6909 8.2348
13 HA12 H OCH2CH3 8.4055 8.3356 8.9546
14 HA13 H OCH2CH2CH3 8.394 8.3399 8.4068
15 HA14 H O(CH)(CH3)2 8.3399 8.3544 8.8646
16 HA15 F OH 8.1736 8.338 7.8714
17 HA16 F OCF3 8.0725 8.6169 8.9678
18 HA17 I Br 8.1664 8.4521 7.8346
19 HA18 F OCH2CH2CH3 8.231 8.2586 8.2285
 20 HA19 Cl OH 8.23 8.4359 8.1055
21 HA20 Cl OCF3 8.1152 8.7166 9.1253
22 HA21 Cl OCH2CH3 8.2613 8.3355 8.1845
23 HA22 SH(OCH3)2 N(Et)2 10.5965 10.6763 9.8133
24 HA23 SH(OCH3)2 N(CH3)2 10.3721 10.6949 8.4701
25 HA24 CH3 N(CH3)2 7.9472 8.1689 8.5679
26 HA25 CH3 N(Et)2 8.5056 8.3512 9.3682
27 HA26 CH3 Br 7.871 8.3533 8.737
28 HA27 SH(OCH3)2 Br 10.0642 10.8753 9.1535
29 HA28 Br Br 8.1606 8.4901 7.8566
30 HA29 Na Br 11.4432 10.5554 8.2489
31 HA30 OH OCH2CH2CH3 8.2341 8.0852 9.2701
compounds that have better activity than compound 18

Hydrogen bond
Hydrogen bond binding region OH binding region
R1 R1

R2

N
Hydrogen bond
binding region Bulky, electron-donating, hydrophobic, and
hydrophilic, and substituent favoured region
Hydrogen bond binding region

8.8
8.7
CoMFA
8.6
Predict pIC50 by CoMFA and CoMSIA

8.5 CoMSIA
8.4
8.3
8.2
8.1
8
7.9
7.8
7.7
HA5
HA1
HA2
HA3
HA4

HA6
HA7
HA8
HA9
18

HA10
HA11
HA12
HA13
HA14
HA15

Compound
 12

Predict pIC50 by CoMFA and CoMSIA

11.5
CoMFA
11
10.5 CoMSIA
10
9.5
9
8.5
8
7.5
7

HA28
18
HA16
HA17
HA18
HA19
HA20
HA21
HA22
HA23
HA24
HA25
HA26
HA27

HA29
HA30
Compound

4. Conclusion
Physico-chemical pretread that affects breast anticancer activity of
pyridine derived compounds as inhibitors p90 Ribosomal S6 Kinase II (RSK II) is
a steric, electrostatic and hydrophobic parameter based on contour map
interpretation. There are 11 other design compounds that are predicted to have
better activity than the experimental 18 compounds based on the amount of pIC50
CoMFA and CoMSIA predictions obtained.

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1. Cari tentang sifat R2 apakah elektronegatif atau elektropositif dari semua

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