Molecular Diversity

https://doi.org/10.1007/s11030-019-10026-9

ORIGINAL ARTICLE

Predictive QSAR modeling for the antioxidant activity of natural

compounds derivatives based on Monte Carlo method
Shahin Ahmadi1 · Hosein Ghanbari1 · Shahram Lotfi2 · Neda Azimi3

Received: 13 October 2019 / Accepted: 23 December 2019

© Springer Nature Switzerland AG 2020

Abstract
In this research, QSAR modeling was carried out through SMILES of compounds and on the basis of the Monte Carlo
method to predict the antioxidant activity of 79 derivatives of pulvinic acid, 23 of coumarine, as well as nine structurally non-
related compounds against three radiation sources of Fenton, gamma, and UV. QSAR model was designed through CORAL
software, as well as a newer optimizing method well known as the index of ideality correlation. The full set of antioxidant
compounds were randomly distributed into four sets, including training, invisible training, validation, and calibration; this
division was repeated three times randomly. The optimal descriptors were picked up from a hybrid model by the combination
of the hydrogen-suppressed graph and SMILES descriptors based on the objective function. These models’ predictability was
assessed on the sets of validation. The results of three randomized sets showed that simple, robust, reliable, and predictive
models were achieved for training, invisible training, validation, and calibration sets of all three models. The central decrease/
increase descriptors were identified. This simple QSAR can be useful to predict antioxidant activity of numerous antioxidants.
Graphic abstract

120 Training
Invisible training
Calibration
100
Validation
Predicted Fenton antioxidant activity

80

60

40

20

-20
-20 0 20 40 60 80 100 120
Experimental Fenton antioxidant activity

Keywords QSAR · Antioxidant activity · CORAL software · Monte Carlo

Electronic supplementary material The online version of this

article (https​://doi.org/10.1007/s1103​0-019-10026​-9) contains
supplementary material, which is available to authorized users.

Extended author information available on the last page of the article

13
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Introduction
Antioxidants are chemical molecules that deferment autoxi-
dation either by preventing the formation of free radicals or
interrupting the dissemination of free radicals. Free radicals
are perpetually produced via many biological or chemical
processes, and also they can emerge spontaneously [1].
Many factors assist the formation of free radicals, for
example smoking, consuming alcohol or certain types of
food, exposing to UV and ionizing radiation (such as γ-rays),
ozone, or by low-molecular-weight complexes of transition
state metals, such as iron via the Fenton reaction. These
compounds have a key part in many physiological, biologi-
cal, and pathological conditions. In biological systems, they
are usually defined as reactive molecules containing oxy-
gen, nitrogen, and sulfur. Thus, they are related to material
degradation, food deterioration, as well as many different
human diseases, including degenerative eye, cardiovascular
disease, diabetes, Alzheimer’s, cancer, and neurodegenera-
tive diseases. Therefore, the free radical formation can be
regulated by antioxidants through different mechanisms. The
effectivity of antioxidants is associated with the activation
energy, rate constants, oxidation–reduction potential, and
antioxidant solubility [2–6].
In this context, the plant foods containing a large num-
ber of antioxidants, such as tocopherols, ascorbic acid,
glutathione, or natural antioxidants, can prevent human dis-
ease. Also, natural antioxidants prove to be suitable addi-
tives in cosmetic products, foods, and food supplements
[7, 8]. Pulvinic acids and coumarine derivatives are natural
compounds; the former is orange pigment found in lichens
and mushrooms, and the latter found in a variety of plant
sources, green plants in particular [9, 10]. These compounds
and their derivatives display various biological activities,
such as antimicrobial [11], antiviral, antitumor, antifungal
[12], cytotoxic [13], as well as anti-inflammatory, antial-
lergic, anticarcinogenic, hepatoprotective, and antioxidant
activities [9].
The ionizing radiation is used in medical and industrial
sectors, such as cancer diagnosis and treatment, as well as
the power supply in nuclear plants. There are many phar-
macological approaches to decrease the detrimental conse-
quences of radiation [14–16]. Among them, antioxidants can
be used as radiation protection agents. These compounds
can effectively scavenge free radicals by trapping them or
absorbing radiations [5, 17]. The ability of antioxidants
against free radicals can be tested in vivo or in vitro, given
their disadvantages, such as being expensive, time-consum-
ing, and questionable due to ethical reasons (animal sacri-
fice) [18].
Quantitative structure–activity relationship (QSAR)
is a powerful theoretical technique to predict the activity
13
Molecular Diversity
of compounds. However, the application of a predicting
model, which may rapidly evaluate the potential activity
of compounds, can appear as an interesting alternative in
determining activities of chemical compounds experimen-
tally. Various multivariate linear and nonlinear techniques
can be employed to deduce correlation models between the
molecular structure and biological activities, including mul-
tiple linear regression (MLR) [19–28], partial least squares
(PLS) [29, 30], principal component regression (PCR) [28],
artificial neural networks (ANN) [31], and support vector
machine (SVM) [31].
For the last two decades, the QSAR models have been
quickly developing and broadly applied by chemists for pre-
dicting chemical properties/biological activities of different
compound types. Nowadays, the QSAR technique is applied
in the correlation between chemical structure and activity of
certain antioxidants. For example, Jorge et al. built a QSAR
model through Dragon software and the neural network tech-
nique founded on the MLP (multilayer perceptron) to pre-
dict radical scavenging ability of 1373 chemical compounds.
Their models indicated an acceptable performance for the
training (R2 = 0.713) and test set (Q2ext = 0.654) [32]. In an
additional work, Le Roux et al. presented a QSAR model
for predicting the antioxidative potency of 30 derivatives
of pulvinic acid toward Fenton condition and UV irradia-
tion based on counter-propagation artificial neural networks
(CP-ANN). They aimed to predict 80 novel molecules with
high antioxidant activity for further consideration of carry-
ing out a chemical synthesis. Among them, they found that
coumarine derivative has excellent protective potency under
UV irradiation and was moderate in Fenton conditions [18].
Moreover, Alisi et al. performed a QSAR to predict
antioxidant activities of the 47 curcumin derivatives based
on the DPPH (2, 2-diphenyl-1-picrylhydrazyl) assay by
genetic function algorithm (GFA) with satisfactory internal
and external validations [33]. Martinčič et al. obtained the
antioxidant activity for a series of coumarine and pulvinic
acid derivatives experimentally and modeled the activity
of the compounds based on CP-ANN, SVR, and MLR to
discover new compounds with high antioxidant properties.
Ten new compounds were demonstrated by the gained data
from chemical classes of the tetronic acid and barbituric acid
with promising antioxidant activity, which is comparable or
even superior to certain standard antioxidants [31]. Recently,
Ahmadi et al. constructed a QSAR model to predict the radi-
cal scavenging activities of 96 natural antioxidants on the
basis of the atomic orbitals’ graph by CORAL. The QSAR
models validated internally and externally and had satisfied
R2 and Q2 values for training and validation sets [4].
Here, the data set on the activity of antioxidants from
Martinčič et al. was utilized. They constructed three QSAR
models for this data set based on combination descriptors
from Codessa, Dragon, as well as Volsurf software, and
Molecular Diversity
utilizing multiple linear regression (MLR), counter-prop-
agation artificial neural networks (CP-ANN), as well as
support vector regression (SVR) [31]. This research aims
to assess CORAL-software-based (http://www.insil​ico.eu/
coral​) QSAR models for antioxidant activity of some natural
compounds and the assessment of the IIC as a predictability
criterion. The CORAL software uses the basic molecular-
input line-entry system (SMILES) for the rapidly obtained
chemical molecules. Requiring no molecular optimization
and saving a lot of time and money, it has an important role
in the molecular design process. Furthermore, the con-
structed models can be interpreted in CORAL software,
but the model interpretation based on 3D descriptors and
via other linear or nonlinear multivariate calibrations (e.g.,
PLS, PCR, and ANN) is not simple. In CORAL software,
according to the model results for increasing and decreasing
descriptors and as a result of QSAR modeling, new com-
pounds can be easily and rapidly designed with high anti-
oxidant activity. This is not the case for many QSAR models
built with 3D descriptors and multivariate calibration such
as PLS, PCR, and ANN.
Method
Data set
The experimental data concerning the antioxidant activity
of compounds containing 79 derivatives of pulvinic acid, 23
derivatives of coumarine, as well as nine structurally non-
related compounds were obtained from Martinčič et al. [31].
The antioxidant activities of compounds have been defined
through three various sources of radicals: gamma radiation,
UV radiation, as well as Fenton reaction [6, 18]. For mod-
eling objectives, the terms Fenton, UV, as well as gamma
activity will be utilized in the text once discussing the anti-
oxidant activity of various molecules moving forward. Fen-
ton and UV activities were assessed utilizing 100 μM of
each compound, whereas the gamma activity assay was per-
formed utilizing a concentration of 50 μM. All the activities
were expressed as a thymidine percentage, which continued
to be intact after being subjected to the source of radicals in
the antioxidant presence. Both for Fenton and UV activities,
in the data set, all the compounds were assessed experimen-
tally, whereas for the gamma activity, only 91 compounds
were tested. Through the free software BIOVIA Draw 2016,
the antioxidant molecular structures were transmuted into
the canonical SMILES. Randomly, the data set was divided
into sets of training, calibration, and validation. Different
numbers of compounds were used for training (e.g., training,
invisible training), calibration, and validation set, because
the data set is structurally diverse. However, the models do
not acquire any proper statistical quality for cross-validation
and external validation with more than 10 percent of vali-
dation set. Finally, QSAR models with three random splits
were divided into the training (about 80%), calibration
(about 10%), and validation (about 10%) and an effective sta-
tistical quality was obtained for training and validation sets.
Descriptors
The utilized optimal descriptors in this study to build the
QSAR model are a combination of hydrogen suppressor
graph (HSG) and SMILES descriptors.
The optimal descriptors of correlation weights to predict
the antioxidant activity of compounds have been defined as
follows:
Activity = C0 + C1 × DCW(T ∗ , N ∗ ) (1)
where T* is optimal for the threshold to define rare molecu-
lar features. N* is the optimal number of epochs in the opti-
mization [4, 34, 35].
The hybrid model is defined through SMILES and graph
descriptor combination as the following equation:
DCW(T ∗ , N ∗ ) = SMILES DCW(T ∗ , N ∗ ) + Graph DCW(T ∗ , N ∗ )
(2)
The optimal graph-based descriptor (DCW) is computed
as the following equation:
( ) ∑
HSG
( ) ( )
DCW(T, Nepoch ) = CW C5 + CW C6 + CW pt3k
∑ (0 ) ∑ (1 ) ∑
CW 2 ECk
( )
+ CW ECk + CW ECk +
(3)
where C5 and C6 denote the presence of five-and six-member
rings, respectively; pt3k descriptor is the path numbers of
length 3 that starts from k-vertex. 0 ECk , 1 ECk , and 2 ECk are
the hierarchy of Morgan’s extended connectivity.
SMILES
DCW(T, Nepoch ) = CW(HARD) + CW(BOND)
+
∑ ( ) ∑
CW Sk +
( )
CW SSk
(4)
where HARD is the association of BOND, NOSP, and
HALO in united structural code, and Sk and SSk are a com-
bination of one or two symbols in SMILES representa-
tion, respectively. The CW(x) is a correlation weight for a
SMILES attribute or an HSG invariant.
For Fenton activity modeling, a hybrid model was made
from a combination of EC0, EC1, EC2, Sk, SSk, and HARD.
For UV, a combination of EC0, EC1, EC2, Sk, SSk, NOSP,
and HARD was used. Finally, for gamma, a hybrid model
from the combination of EC0, EC1, EC2, pt3, C5, C6, Sk,
SSk, and HARD was used.
There exist two target functions to create the QSAR
model in CORAL software: target function on the basis of
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 Molecular Diversity

the balance of correlation (TF1) and target function based (R2), concordance correlation coefficient (CCC), the index of
on the index of ideality (TF2) [36]. ideality of correlation (IIC), cross-validated correlation coef-
ficient (Q2), correlation coefficient for external data (Qext2),
TF1 = RTRN + RiTRN − ||RTRN − RiTRN || × c (4) standard error of estimation (s), mean absolute error (MAE),
Fischer ratio (F), and novel metrics ( R2m and MAE-based
where RTRN and RiTRN are correlation coefficients between
metric).
an endpoint’s perceived and computed values for the training
and invisible training sets, respectively, and c is empirical
constant.
Applicability domain
In this work, ­TF2 has been applied:
One of the OECD concepts for model validation is demon-
TF2 = TF1 + IIC (5) strating the applicability domain (AD) of the QSAR models,
that is, the chemical space, where the model can be applied
where IIC (index of the ideality of correlation) is calculated and is constructed using the “ DefectAK ”, as in Eq. (10) [39]:
through the formula below [37]:
|PTRN (AK )−PCAL (AK )|
(
min − MAECAL , + MAECAL
) DefectAK = If (AK ) > 0
NTRN (AK )+NCAL (AK ) (10)
IIC = rCAL × ( ) (6) DefectAK = 1 If (AK ) > 0
max − MAECAL , + MAECAL
PTRN (AK ) presents the attribute AK presence probability
where rCAL is the correlation coefficient value between an
in the training set, as shown in Eq. (11):
endpoint’s experimental and computed values for the cali-
bration set. NTRN (AK )
MAE is mean absolute error, which is computed based on PTRN (AK ) = (11)
NTRN
the following equation:
−
PTRN (AK ) denotes the attribute AK presence probability in
N
−
MAECAL =−
1 ∑| |
|Δ | Δ < 0, − N is the number of Δy < 0
the training set, as represented in Eq. (12):
N y=1 | y | y
NCAL (AK )
(7) PCAL (AK ) = (12)
NCAL
N+
+ 1 ∑| |
MAECAL = + |Δ | Δ ≥ 0, + N is the number of Δy ≥ 0 NTRN (Ak) shows the number of Ak in the set of training;
N y=1 | y | y
NTRN signifies the total number of the training set; NCLT(Ak)
(8)
denotes the number of A ­ k in the calibration set; NCAL speci-
Δy = Obsy − Calcy (9) fies the total number of the calibration set.
where Obsy is experimental cell viability (%), and Calcy is AK
∑
calculated cell viability (%). DefectMolecule = DefectAK . (13)
Now, the values of T and N are defined from 1 to 3 and 1 i=1

to 30, respectively. By SMILES, the substance is encompassed in the domain

After searching for the response surface of TF2 for the of applicability if:
validation set, T* and N* are obtained with the maximum
value of TF2 between antioxidant activity and DCW (T*, Defectmolecule < 2 × DefectTRN (14)
N*).
where DefectTRN is the mean of the Defectmolecule over the
Validation of the QSAR model set of training.

The main objective of any QSAR modeling is to establish Model interpretation

a robust model with the capacity to predict the activity of
novel compounds objectively, reliably, and precisely [38].
There are some criteria to evaluate the predictive capabil-
ity of QSAR models, including internal validation or cross-
validation, external validation and data randomization, and
Y-scrambling.
Various standard statistical criteria were applied to vali-
date the QSAR models, including the correlation coefficient
Mechanical interpretation of the studied phenomena is pos-
sible by the developed QSAR models. One may extract three
classes of features with the numerical data on the correla-
tion weights in several Monte Carlo optimization runs [34]:
(1) those with a positive value of the correlation weight
in all runs (promoters of the endpoint increase); (2) those
with a negative value of the correlation weight in all runs

13
Molecular Diversity

(promoters of the endpoint decrease); as well as (3) those UV activity model

with both negative and positive values of the correlation
weight in various optimization runs. Such properties have Split 1
an unclear part (that may not be classified as an increase/
UV activity = −3.3205(±0.3548) + 0.5704(±0.0066) × DCW(1, 28)
decrease promoter of the endpoint).
(21)
Split 2
Results and discussion UV activity = −6.5173(±0.2603) + 0.6680(±0.0052) × DCW(1, 26)
(22)
QSAR models Split 3

In the equations below, the QSAR models for the antioxi-
dant activity of natural compounds against UV radiation,
gamma radiation, as well as Fenton reaction are obtained on
the basis of the Monte Carlo optimization method for three
random data splits according to ­TF2:
Fenton activity model
Split 1
Fenton activity = 14.4150(±0.3316) + 1.9843(±0.0237)
(15)
× DCW(1, 30)
UV activity = −4.8531(±0.5135) + 0.4683(±0.0069) × DCW(1, 10).
(23)
The statistical criteria of QSAR models to predict the
antioxidant activity of compounds based on Eqs. 15–23 are
represented in Table 1. The satisfactory statistical criteria
of models in Table 1 indicate that these robust models have
excellent performance and may be utilized to predict the
antioxidant activity of compounds.
These models are quite appropriate for all splits. Further-
more, all constructed models’ reliability is further assessed
through the randomization method (Y-scrambling) to exam-
ine their robustness. A model may be defined as robust if CR2
p

Split 2 is greater than 0.5 [34]. Table S1 shows SMILES of antioxi-

dant compounds, the set of each compound, their observed
Fenton activity = −40.5829(±0.6171) + 2.8038(±0.0282) and calculated of Fenton, UV, and gamma activity, and the
× DCW(1, 28) applicability domain of the compounds in three splits as
(16) Supplementary Data. Figure 1a–c shows graphical result
Split 3 models derived of split 1 from Fenton, UV, as well as gamma
activity, respectively. These plots indicate an excellent
Fenton activity = −5.7652(±0.460) + 1.8719(±0.0251)
agreement between predicted and experimental data.
× DCW(1, 13) Table S2 contains the outlier molecules of each split and the
(17) R2Val results of removing them. Based on Table S2 results for
Fenton activity, after removing the outliers, the derived
Gamma activity model model from split 3 with the highest (0.9762) is the best
model. For UV activity, with removing five molecules, the
Split 1 derived model from split 2 with the highest R2Val (0.9263) is
the best one. Moreover, gamma activity removing four mol-
Gamma activity = −3.9081(±0.6500) + 1.0488(±0.0110)
ecules, the derived model from split 3 with R2Val (0.9762) is
× DCW(1, 22) the best. Table 2 indicates the examples of increase/decrease
(18) promoters for the antioxidant activity of compounds. As
Split 2 observed in Table 2, there is a suitable distribution for the
frequencies of these attributes in training and calibration
Gamma activity = −8.0740(±0.6581) + 1.0751(±0.0095)
sets, and the valid positive or negative impact of the attrib-
× DCW(1, 29) utes on antioxidant activity of compounds may be con-
(19) cluded. In Fenton activity, the presence of oxygen branching
Split 3 from oxygen atom (O…(…….) is the promoter for the anti-
oxidant activity increase, whereas the presence of double
Gamma activity = −5.2544(± 0.8484) + 0.8831(± 0.0108)
covalent bonds (= ………..) is a promoter for Fenton activity
× DCW(1, 10) decrease. In UV and gamma activity, the presence of at least
(20)
one ring (1………..) is a promoter for antioxidant activity
increase (the low values of activity for molecules No. 30 and

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 Molecular Diversity

Table 1  The summary statistical qualities of the QSAR models obtained for Fenton, UV, and gamma activity for three different random splits
Split Set n R2 IIC Q2 R2m CR2p r̄m2 Δrm2 S MAE F

Fenton
1 Training 49 0.7518 0.8324 0.7311 0.7447 14.5 10.7 142
Invisible training 40 0.8791 0.6288 0.8686 0.8607 12.6 10.3 276
Calibration 13 0.6837 0.8267 0.5539 0.6147 16.7 12.4 24
Validation 8 0.6981 0.7845 0.4727 0.6049 0.6079 0.0060 15.1 12.1 14
2 Training 49 0.7984 0.6701 0.7822 0.7820 12.2 8.6 186
Invisible training 43 0.8116 0.8299 0.791 0.7940 12.8 9.9 177
Calibration 9 0.7673 0.8758 0.5721 0.6777 16.4 13.0 23
Validation 9 0.8625 0.6701 0.6737 0.8184 0.7675 0.1018 13.9 11.8 44
3 Training 48 0.7378 0.7268 0.7143 0.7309 13.1 9.7 129
Invisible training 45 0.7379 0.5494 0.7161 0.7287 16.6 12.0 121
Calibration 9 0.8419 0.9168 0.6219 0.7849 16.6 13.5 37
Validation 8 0.8003 0.6570 0.5248 0.6179 0.6899 0.1440 16.4 12.9 24
Gamma
1 Training 35 0.8357 0.8634 0.8197 0.8159 9.5 7
Invisible training 33 0.8386 0.6751 0.8171 0.8253 10.3 7 161
Calibration 13 0.8571 0.9258 0.8105 0.8228 10.6 8.2 66
Validation 10 0.919 0.8011 0.8851 0.5176 0.6035 0.1718 9.4 7.0 91
2 Training 38 0.8572 0.7495 0.8445 0.8513 9.1 6.2 216
Invisible training 31 0.9171 0.7008 0.9069 0.8946 10.7 8.3 321
Calibration 13 0.8100 0.8999 0.7365 0.7720 12.0 8.3 47
Validation 9 0.7955 0.7585 0.6791 0.6305 0.7115 0.1619 11.4 10.1 27
3 Training 35 0.7983 0.8438 0.778 0.7872 10.4 8.0 131
Invisible training 30 0.8894 0.7991 0.8762 0.8811 12.3 9.8 225
Calibration 14 0.8934 0.9452 0.8579 0.8651 13.7 10.4 101
Validation 12 0.8583 0.4606 0.8003 0.5641 0.6456 0.1631 11.8 9.2 61
UV
1 Training 41 0.8417 0.6499 0.8248 0.8230 4.4 3.2 207
Invisible training 41 0.8485 0.853 0.8337 0.8194 5.1 3.9 218
Calibration 18 0.8099 0.8999 0.7599 0.7760 6.7 5.6 68
Validation 10 0.8030 0.8376 0.7079 0.5148 0.6132 0.1968 5.7 4.4 33
2 Training 44 0.8525 0.9233 0.8411 0.8367 4.68 3.59 243
Invisible training 36 0.8765 0.6832 0.8616 0.8627 5.1 4.11 241
Calibration 16 0.7797 0.8829 0.7172 0.7296 6.5 5.5 50
Validation 14 0.7882 0.6608 0.7110 0.5538 0.6487 0.1898 5.04 4.22 45
3 Training 44 0.7926 0.7419 0.7684 0.7894 5.02 4.19 161
Invisible training 43 0.8161 0.7865 0.8010 0.8034 5.65 4.48 182
Calibration 12 0.7682 0.8761 0.6853 0.7289 6.19 4.82 33
Validation 11 0.7771 0.6392 0.6707 0.5659 0.6604 0.1890 4.94 3.54 31

31 confirm this well), whereas the presence of carbon with
branching (C…(…….) is a promoter for a decrease in UV
and gamma activity.
The classification of molecular attributes as promoters of
the studied activity increase or decrease is done on the basis
of the model interpretation section. Antioxidant compound
24 was selected as the template molecule for interpretation
and examination of increasing and decreasing descriptors
to design new antioxidant compounds. Seven new modeled
antioxidants based on certain increasing or decreasing
promoters of attributes and the effects of new activities of
designed structures are calculated based on QSAR models
of split 1. The structure, SMILES notation, and predicted
activity of all designed antioxidants are given in Table 3.
One of the identified promoters in an increase of the Fen-
ton activity is the presence of oxygen branching from oxy-
gen atom (O…(…….); one hydroxyl group is added to the
template molecule M0 (molecule 24). The calculated Fenton

13
Molecular Diversity

Fig. 1  The graph of the (a) 120 Training

experimental versus predicted Invisible training
values for different antioxidant Calibration
activities, based on split 1 for: a 100 Validation

Predicted Fenton antioxidant activity

Fenton activity; b gamma activ-
ity; c UV activity 80

60

40

20

-20
-20 0 20 40 60 80 100 120
Experimental Fenton antioxidant activity
(b) 120
Training
Invisible training
Calibration
100
Predicted gamma antioxidant activity

Validation

80

60

40

20

0
0 20 40 60 80 100 120
Experimental gamma antioxidant activity
(c) 60
Training
Invisible training
Calibration
50 Validation
Predicted UV antioxidant activity

40

30

20

10

-10
-10 0 10 20 30 40 50 60
Experimental UV antioxidant activity

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 Molecular Diversity

Table 2  The correlation weights, number of each attribute in each set, and interpretation of most important attributes for increasing and decreas-
ing of Fenton, UV, and gamma activity of split 1
Activity CW CW CW NaT NbiT NcC Defect ­(MFk) Interpretation of descriptor
­(MFk) in ­(MFk) in ­(MFk) in
run 1 run 2 run 3

Fenton Increase
O…(……. 0.81 0.56 0.75 49 39 13 0 Branching of molecular skeleton started from oxygen
EC2-C…19.. 1.81 1.62 1.37 47 33 11 0.0019 The presence of Morgan connectivity second order for
carbon equal to 19
EC1-C…9… 5.38 4.94 4.56 45 34 12 0.0001 The presence of Morgan connectivity first order for
carbon equal to 9
Decrease
(……….. − 1.00 − 0.44 − 0.88 49 39 13 0 Branching
=……….. − 1.13 − 1.31 − 0.75 49 39 13 0 The presence of double bond
C……….. − 0.75 − 0.87 − 0.75 49 40 13 0 The presence of aliphatic carbon atom
O……….. − 1.81 − 1.68 − 0.81 49 39 13 0 The presence of oxygen atom
C… = ……. − 1.38 − 0.87 − 2.38 48 37 13 0.0003 The presence of aliphatic carbon atom with double bond
EC0-O…2… − 2.62 − 1.75 − 1.19 48 37 13 0.0003 The presence of Morgan connectivity zero order for
oxygen equal to 2
Gamma Increase
1……….. 4.13 3.63 4.37 44 42 12 0 The presence of one ring
EC0-O…1… 0.50 0.62 0.50 44 43 12 0 The presence of Morgan connectivity zero order for
oxygen equal to 1
EC1-C…7… 2.19 2.31 2.00 44 40 12 0 The presence of Morgan connectivity first order for
carbon equal to 7
O…C……. 2.31 2.75 2.88 44 40 12 0 The presence of oxygen connected to the aliphatic
carbon
2……….. 3.63 4.75 3.75 42 41 10 0.0023 The presence of two rings
Decrease
(……….. − 0.44 − 0.31 − 0.57 44 43 12 0 Branching
C…(……. − 0.38 − 0.50 − 0.50 44 41 12 0 The presence of aliphatic carbon with branching
O… = ……. − 0.75 − 0.88 − 0.50 44 42 12 0 The presence of oxygen atom with double bond
UV Increase
1……….. 3.07 3.50 2.69 33 33 13 0.0012 The presence of one ring
PT3-O…3… 2.38 0.43 0.18 32 33 13 0.0019 The presence of the path of length 3 equal to 3 for
oxygen atom
PT3-C…4… 1.13 1.00 0.63 32 32 13 0.0019 The presence of the path of length 3 equal to 4 for
carbon atom
PT3-C…5… 2.63 2.56 3.69 32 33 11 0.0016 The presence of the path of length 3 equal to 5 for
carbon atom
Decrease
EC0-C…2… − 1.00 − 0.75 − 1.07 34 33 12 0.0011 The presence of Morgan connectivity zero order for
carbon atom equal to 2
C…(……. − 1.13 − 0.56 − 1.50 32 33 13 0.0019 The presence of aliphatic carbon with branching

activity for the designed antioxidant M1 was 61.5, more
than 20 percent higher than the Fenton activity of molecule
M0. The presence of double covalent bonds (= ………..) is
identified as decreasing promoters for Fenton activity; the
molecule M0 modified with an ethylene group to M1, as well
as this compound activity, decreases from 40.4 to 33.7. Mol-
ecule M3 has a hydroxyl group addition to five-membered
rings of M0 that indicates the presence of oxygen associated
with the aliphatic carbon as increasing promoters; gamma
activity increases from 61.5 to 64.6. Molecules M4 and M5
modified by adding one or two isopropyl groups to the M0
template are concluded from carbon branching from (C…
(…….) as decreasing promoters; gamma activity reduces
from 61.5 to 38.7 and 9.7 for M4 and M5, respectively. Also,
the branching effect of aliphatic carbon atom investigated
by designing molecules M6 and M7 through adding one
and two isopropyl groups to the M0 template is concluded
from carbon with branching from (C…(…….) as decreasing

13
Molecular Diversity

Table 3  The structure, SMILES notation, and predicted activity of all designed antioxidants (the added group showed as blue color)
No. Structure and SMILES Exp. Fenton activity Exp. gamma activity Exp. UV activity

M0
40.4 61.5 27.2

OC1=C(C(=O)OC1)c2ccccc2 Predicted Fenton activity from Eq. 15

61.5 The presence of oxygen with branching from oxygen

M1
atom (O...(.......) as increasing promotors

OC1=C(C(=O)OC1)c2cccc(O)c2 Predicted Fenton activity from Eq. 15

The presence of double covalent bonds (=...........) as

M2 33.7
decreasing promotors

OC1=C(C(=O)OC1)c2cccc(C=C)c2 Predicted gamma activity from Eq. 18

The presence of oxygen connected to the aliphatic carbon

M3 64.6
as increasing promotors

OC1OC(=O)C(=C1O)c2ccccc2 Predicted gamma activity from Eq. 18

The presence of carbon with branching (C...(.......) as

M4 38.7
decreasing promotors

CC(C)c1ccc(cc1)C2=C(O)COC2=O Predicted gamma activity from Eq. 18

The presence of more carbon with branching (C...(.......)

M5 9.7
as decreasing promotors

CC(C)c1ccc(C2=C(O)COC2=O)c(c1)C(C)C Predicted UV activity from Eq. 21

The presence of carbon with branching (C...(.......) as

M6 20.1
decreasing promotors

CC(C)c1ccc(cc1)C2=C(O)COC2=O Predicted UV activity from Eq. 21

The presence of more carbon with branching (C...(.......)

5.5
as decreasing promotors

M7 CC(C)c1ccc(C2=C(O)COC2=O)c(c1)C(C)C

promoters; UV activity reduces from 27.2 to 20.1 and 5.5 for
M6 and M7, respectively.
Table 4 indicates the statistical characteristics of reported
QSAR models for the antioxidant activity of the studied
compounds in the previous literature [31]. These statistical
parameters show the comparison of suggested models with
the other ones presented in previous studies. In contrast to
the commonly conformation-dependent QSAR methods,
CORAL is capable of generating molecular descriptors and
developing QSAR models with appropriate mechanistic
interpretation without any 3D optimization that has high
computational costs and long developing time. According to
Table 4, R2training of the models developed by Martinčič et al.
is comparable by the present study as a proper QSAR model.
We used about 10% of the data for validation because the
data set is structurally diverse. Using the larger data set for
the training set, we obtained a good statistical quality for the
test set. Also, we designed some new molecules based on

13

Table 4  The comparison No. Radiation source
ntraining
between characteristics of
previous models from published
literature and the current study
1 Fenton
2 UV
3 Gamma
4 Fenton 101
5 UV 100
6 Gamma
decreasing and increasing descriptors and showed the effect
of some parameters on antioxidant activity.
Conclusion
In the current research, new QSAR models were developed
to predict the antioxidant activity of a different set of tested
antioxidants using three various radical sources, including
Fenton reaction, gamma radiation, and UV radiation. The
QSAR models were created via CORAL software based on
the Monte Carlo optimization technique. The predictabilities
of the suggested models were evaluated through appropriate
statistical criteria. However, all of the established models
were appropriate to predict the novel antioxidant candi-
dates and could be assessed before synthesis. The hybrid
attributes with IIC target specified a meaningful relationship
between antioxidant activity and certain global HSG-type
graphs along with SMILES features, which were applied to
achieve the correlation weights for molecular attributes via
the Monte Carlo technique.
A noble mechanistic interpretation of the increasing and
decreasing attributes has been made by analyzing the cor-
relation weights of different molecular attributes gained in
three Monte Carlo optimization runs. Such descriptors were
applied to design new and more potent antioxidants in silico
approaches.
Acknowledgements The authors are thankful to Dr. Alla P. Toropova
and Dr. Andrey A. Toropov for providing the CORAL software.
Compliance with ethical standards
Conflict of interest The authors declare no conflicts of interest.
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Shahin Ahmadi1 · Hosein Ghanbari1 · Shahram Lotfi2 · Neda Azimi3
* Shahin Ahmadi
ahmadi.chemometrics@gmail.com
1 Department of Chemical Engineering, Kermanshah Branch,
Department of Chemistry, Kermanshah Branch, Islamic
Azad University, Kermanshah, Iran
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Publisher’s Note Springer Nature remains neutral with regard to
jurisdictional claims in published maps and institutional affiliations.
2
Department of Chemistry, Payame Noor University (PNU),
19395‑4697 Tehran, Iran
3
Islamic Azad University, Kermanshah, Iran
13