Computational Biology and Chemistry 95 (2021) 107597

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Computational Biology and Chemistry

journal homepage: www.elsevier.com/locate/cbac

Virtual screening of dipeptidyl peptidase-4 inhibitors using quantitative

structure–activity relationship-based artificial intelligence and molecular
docking of hit compounds
Oky Hermansyah a, Alhadi Bustamam b, Arry Yanuar a, *
a
Laboratory of Biomedical Computation and Drug Design, Faculty of Pharmacy, Universitas Indonesia, Depok 16424, Indonesia
b
Department of Mathematics, Faculty of Mathematics and Natural Sciences, Universitas Indonesia, Depok 16424, Indonesia

A R T I C L E I N F O A B S T R A C T

Keywords: Dipeptidyl peptidase-4 (DPP-4) inhibitors are becoming an essential drug in the treatment of type 2 diabetes
Artificial intelligence mellitus; however, some classes of these drugs exert side effects, including joint pain and pancreatitis. Studies
DPP-4 suggest that these side effects might be related to secondary inhibition of DPP-8 and DPP-9. In this study, we
KNIME
identified DPP-4-inhibitor hit compounds selective against DPP-8 and DPP-9. We built a virtual screening
Machine learning
QSAR
workflow using a quantitative structure–activity relationship (QSAR) strategy based on artificial intelligence to
Virtual screening allow faster screening of millions of molecules for the DPP-4 target relative to other screening methods. Five
regression machine learning algorithms and four classification machine learning algorithms were applied to
build virtual screening workflows, with the QSAR model applied using support vector regression (R2pred 0.78)
and the classification QSAR model using the random forest algorithm with 92.2% accuracy. Virtual screening
results of > 10 million molecules obtained 2 716 hits compounds with a pIC50 value of > 7.5. Additionally,
molecular docking results of several potential hit compounds for DPP-4, DPP-8, and DPP-9 identified CH0002 as
showing high inhibitory potential against DPP-4 and low inhibitory potential for DPP-8 and DPP-9 enzymes.
These results demonstrated the effectiveness of this technique for identifying DPP-4-inhibitor hit compounds
selective for DPP-4 and against DPP-8 and DPP-9 and suggest its potential efficacy for applications to discover hit
compounds of other targets.

1. Introduction
Dipeptidyl peptidase-4 (DPP-4) (EC 3.4.14.5) inhibitors are impor­
tant oral antidiabetic drugs for treating type 2 diabetes (T2DM). Sita­
gliptin was reported in 2006 as the first DPP-4 inhibitor agent, and since
then, this class of drugs has increasingly shifted the role of sulfonylurea
in T2DM treatment according to national and international guidelines.
The drugs work differently from most other antidiabetic drugs. DPP-4
inhibition stimulates the pancreas to produce and release insulin while
reducing or normalizing body weight without causing hypoglycemia
(Alam et al., 2018; Chylewska et al., 2018; Gallwitz, 2019;
Popovic-Djordjevic et al., 2018; Sesti et al., 2019).
Some commercially available DPP-4 inhibitors are well-tolerated,
whereas others have side effects, ranging from joint pain to
pancreatitis, and are related to the secondary inhibition of enzymes with
high-sequence homology to DPP-4 (e.g., DPP-8 and DPP-9) (Huan et al.,
2015; Patel and Ghate, 2014). Therefore, there is a need to develop
novel DPP-4 inhibitors selective against DPP-8 and DPP-9 enzymes.
Novel DPP-4 inhibitors can be developed through high-throughput
screening, which is generally performed by pharmaceutical com­
panies. An alternative is the computer-aided drug design through virtual
screening (Hughes et al., 2011; Pei et al., 2020; Shamsara, 2019; Wang
et al., 2019) of large databases containing millions of compounds, such
as ChEMBL (Gaulton et al., 2012) and PubChem (Kim et al., 2016). A
virtual screening method developed using a quantitative structur­
e–activity relationship (QSAR) strategy (regression or classification)
capable of predicting the selectivity of a molecule for DPP-4 can reveal
the relationship between molecular structures represented by

Abbreviations: DL, Deep Learning; XGBoost, XGBoost Tree Ensemble; RF, Random Forest; MLR, Multiple Linear Regression; SVR, Support Vector Regression; SVM,
Support Vector Machine.
* Correspondence to: Faculty of Pharmacy, Universitas Indonesia, Depok 16424, Indonesia.
E-mail address: arry.yanuar@ui.ac.id (A. Yanuar).

https://doi.org/10.1016/j.compbiolchem.2021.107597
Received 17 April 2021; Received in revised form 25 October 2021; Accepted 26 October 2021
Available online 30 October 2021
1476-9271/© 2021 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
O. Hermansyah et al.
Fig. 1. QSAR workflow for modeling DPP-4 inhibitors.
descriptors or fingerprints with potential hit compounds.
In this study, we performed virtual screening by developing a
workflow (Kausar and Falcao, 2018; Ramesh and Muthuraman, 2020; P.
Mazanetz et al., 2012; Santos et al., 2019; Wójcikowski et al., 2019) that
uses QSAR classification models to predict hit compounds, followed by
QSAR regression to assess their values (Ramesh and Muthuraman,
2020). Additionally, we employed artificial intelligence (AI) techniques
to incorporate a supervised learning algorithm into the QSAR process
(Bitencourt-Ferreira et al., 2021; Bitencourt-Ferreira and de Azevedo,
2019a; da Silva et al., 2020; Kumar et al., 2018) to allow faster evalu­
ation of millions of molecules relative to other virtual screening methods
(Neves et al., 2018). Previous studies have employed AI-based QSAR
analysis of DPP-4 inhibitors (Al-Fakih et al., 2019; Gu et al., 2013;
Sokolović et al., 2017); however, they considered only certain com­
pound derivatives and small datasets, thereby limiting their predictive
ability to only those derivatives. The principle of QSAR suggests that
similar structures have similar activities (Martin et al., 2002); therefore,
using a small dataset and a limited number of derivative compounds
makes the prediction bias, especially when screening several com­
pounds. Therefore, our goal was to expand AI-based QSAR to enable the
prediction of DPP-4-inhibitor compounds from larger datasets and
without limitations by the number or type of derivative. Moreover, a
2
Computational Biology and Chemistry 95 (2021) 107597
previous study employed a machine learning approach to
DPP-4-inhibitor screening (Cai et al., 2017); however, their prediction
accuracy was < 90%.
Herein, we developed a QSAR model that meets the QSAR statistical
parameter standard (Golbraikh and Tropsha, 2002; Roy et al., 2015a) for
regression models and the accuracy standard for classification models.
We employed five machine learning regression algorithms (i.e., XGBoost
tree ensemble, random forest, support vector regression, deep learning,
and multiple linear regression) and four machine learning classification
algorithms (i.e., XGBoost tree ensemble, random forest, support vector
regression, and deep learning) (Babajide Mustapha and Saeed, 2016;
Roy et al., 2015b). Further, we used molecular docking to identify hit
compounds selective toward DPP-4 and against DPP-8 and DPP-9 and
related commercially available ligands, including trelagliptin, omar­
igliptin, and carmegliptin (Burness, 2015. Omarigliptin: First Global
Approval. Drugs, 75(16), 2015; Makrilakis, 2019; Mattei et al., 2010;
McKeage, 2015). Commercial compounds were included because they
are expected to exhibit inhibitory constants (Ki) similar to those of po­
tential hit compounds (Huan et al., 2015).
2. Methods
2.1. Dataset
The dataset was downloaded from the ChEMBL website, and it in­
cludes the human DPP-4 target and an IC50 activity filter (https://www.
ebi.ac.uk/chembl/target_report_card/CHEMBL284/). The dataset con­
tained 4 661 compounds after removing empty activity values, salt ions,
and small fragments, with activity units presented as molar values. The
molecular structures were normalized and compound duplication was
determined (Cherkasov et al., 2014; Kausar and Falcao, 2018). The
remaining 3 933 compounds were used as the regression modeling
dataset.
For the QSAR classification models, we used 4 355 compounds from
the ChEMBL database obtained using a scientific literature filter. The
missing values and duplicates were corrected, salt ions and small frag­
ments were removed, and the molecular structure was normalized
(Cherkasov et al., 2014; Kausar and Falcao, 2018), leaving 3 740 com­
pounds. The data were classified as active and inactive compounds, with
pIC50 activities > 7.5 designating active compounds and pIC50 < 6
designating inactive compounds (those with pIC50 between 6.0 and 7.5
were removed) (Cai et al., 2017). The remaining 2 307 compounds were
used for the model development.
2.2. Calculation of descriptors and fingerprints
Descriptor and fingerprint calculations were performed using four
nodes in KNIME (Beisken et al., 2013) (i.e., RDKit descriptor calculation
and fingerprinting and CDK fingerprint and molecular properties)
(Beisken et al., 2013). The total descriptors and fingerprints of each
molecular structure included 17 784 and 19 875 features for the clas­
sification and regression models, respectively.
2.3. Standardization of activities and partitions
The activity of each molecular structure (IC50) was converted into
logarithmic values in molar units [pIC50 = − log (IC50 × 10− 9)] (Selvaraj
et al., 2011). The dataset was randomly partitioned (80%:20%), fol­
lowed by further partitioning to 90%:10%, and 10% was used for
training and 20% as the test dataset (Baldi and Brunak, 2001; Ripley,
1996; Xiong et al., 2020). The training set was used for model con­
struction and validation, and the test dataset was used for internal and
external evaluation of the models (Liu et al., 2018; Mozafari et al., 2020;
Myint et al., 2012).
O. Hermansyah et al. Computational Biology and Chemistry 95 (2021) 107597

2.4. Feature selection
Optimal features were selected using several feature-selection
methods. Dimension reduction was performed with principal compo­
nent analysis, calculation of height correlation, and application of the
random forest algorithm (Silipo et al., 2014). The identified features
were tested using several machine learning models, and those with the
highest accuracy were used as features for modeling.
2.5. Quantitative structure–activity relationship modeling
A previous study proposed rm2(test) for external validation of models
(Roy et al., 2015a), with this value calculated using the square of the
correlation coefficient between actual and predicted activities from the
test dataset. For acceptable predictions, r2m (test) should be < 0.2 when
∆rm2 (test) is > 0.5.
2.7. Evaluation of the classification QSAR model
Internal validation and external validation datasets were used to test
classification model performance. All models were evaluated as follows:

Sensitivity = Recall = TP / (TP + FN) (5)

Five machine learning algorithms were used to build the QSAR
regression models (XGBoost tree ensemble, multiple linear regression, Specificity= TN / (TN + FP) (6)
random forest, deep learning, and support vector regression) and four
were used for the QSAR classification models (XGBoost tree ensemble, Accuracy= (TP + TN) / (TP + FP +TN + FN) (7)
random forest, deep learning, and support vector regression). The par­ F-Measure = 2(Recall × Precision) / (Recall + Precision) (8)
titioned dataset was used to build the machine learning models from
training and validation (Fig. 1). The hyperparameter value of each Precision (FP Rate)= TP / (TP +FP) (9)
model was determined through optimization with a random search (a
A receiver operating characteristic (ROC) plot was used to visualize
combination of 100 experiments), with the hyperparameter showing the
the model behavior according to the area under the ROC curve (AUC),
best performance used for internal and external validation.
with an AUC of 0.5 indicating that the classification model has no
discriminatory power (Gramatica, 2013; Roy et al., 2015a).
2.6. Evaluation of the QSAR regression model
2.8. Testing QSAR model workflow on other targets
To determine goodness-of-fit model performance, we performed
statistical analysis of the regression coefficient (R), determination co­ To assess QSAR workflow implementation, targets from the ChEMBL
efficient (R2), and mean-square error (MSE) for each machine learning database [opioid sigma receptor (CHEMBL287) and a β1 adrenergic
algorithm. Hyperparameter selection was evaluated using the lowest receptor (CHEMBL213)] were used as a modeling dataset to evaluate
root (R)MSE. predictive capability. Activity data for each target was downloaded from
∑(yi − ŷ ) ChEMBL and analyzed with KNIME, and the same five machine learning
R = 1− i
(1) regression algorithms were used for the analysis.
i
(yi − yi )

∑(yi 2.9. Virtual screening using multiple databases

ŷi )2
(2)
−
R2 = 1 − 2
(yi − yi )
i
To identify DPP-4-inhibitor hit compounds, virtual screening was
performed using various databases, including 1 870 461 molecules from
1∑ n
MSE = (yi − ŷi )2 (3) ChEMBL (Davies et al., 2015; Gaulton et al., 2017), 1424986 molecules
n i=1 from PubChem (Kim et al., 2018) (https://ftp.ncbi.nih.gov/pubchem/­
√̅̅̅̅̅̅̅̅̅̅̅̅̅̅̅̅̅̅̅̅̅̅̅̅̅̅̅̅̅̅̅ Compound/CURRENT-Full/SDF/; last update: October 18, 2019), and 7
1∑ n
869 542 molecules from Molport (ftp://molport.com/: last update: 18
RMSE = (yi − ŷi )2 (4)
n i=1 October 2019). These molecules were tested using the QSAR classifica­
tion models to determine their activities. Active molecules were further
where yi is the actual value, ŷi is the predicted value, and yi is the actual processed for similarity testing using the ChEMBL DPP-4-inhibitor data
average value. The minimum value recommended to allow the QSAR to determine whether a hit compound was novel. The Tanimoto coeffi­
regression model to produce a reliable prediction and that of the cor­ cient was used as the similarity descriptor, with a similarity limit of 0.85
relation coefficient (R) for in vivo data was ≥ 0.8 with a coefficient of as a threshold through 166-bit MACCS fingerprinting (Danishuddin,
determination (R2) ≥ 0.6 (Veerasamy et al., 2011). Khan, 2016; Martin et al., 2002).
We used a set of previously described parameters to determine the The activities of the active molecules that met the similarity criteria
external predictability of the QSAR regression models (whether a model were determined using the QSAR regression models. The obtained hit
is satisfactory if all conditions are met) (Golbraikh and Tropsha, 2002): compounds were then evaluated to compare with DPP-4 target decoys
from DUD-E (Mysinger et al., 2012) (http://dude.docking.org/tar­
1. R2(cv) > 0.5 gets/dpp4) to determine whether that the hit compounds were similar to
2. R2(ext) > 0.6 pan-assay interference compounds (Lipinski et al., 2001). We employed
R− R20 Lipinski’s rule of five to determine whether a hit compound qualifies for
3. R2
< 0.1 and 0.85 ≤ k ≤ 1.15 or
potential development as a DPP-4 inhibitor.
R 2
− R′ 20
4. r2
< 0.1 and 0.85 ≤ k’ ≤ 1.15 or
⃒ ⃒ 2.10. Molecular docking of hit compounds with DPP enzymes
5. ⃒R20 − R′ 20 ⃒ < 0.3
Hit compounds with the highest activities were determined from the
where R2(cv) and R2(ext) are the coefficients of determination from in­ virtual screening results, and molecular docking was performed using
ternal validation results and the test data, respectively; R20 and R′ 20 are the DPP-4, DPP-8, and DPP-9 crystal structures obtained from the Pro­
the coefficients of determination between actual and predicted activities tein Data Bank (PDB) (Berman, 2000; Kang et al., 2007). DPP-4 crystal
at zero intercepts and between predicted and actual activities, respec­ structures include various commercially available ligands, such as tre­
tively; and k and k′ are the slopes of the regression line through the lagliptin (PDB: 5KBY) (Grimshaw et al., 2016), alogliptin (PDB: 2ONC)
origin point (Golbraikh and Tropsha, 2002). (Feng et al., 2007), omarigliptin (PDB: 4PNZ) (Biftu et al., 2014), and

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O. Hermansyah et al.
Fig. 2. Analysis of the chemical space. Training set versus test set (external validation) defined by molecular weight (MW) and ALogP. (A) For the regression model,
green symbols (x) are results from the training set, and red symbols (∆) are results from the test set. (B) For the classification model, blue symbols (□) are results from
the training set, and red symbols (∆) are results from the test set.
Fig. 3. Feature selection. Seven features developed to obtain the best method
using four learning models.
carmegliptin (PDB: 3KWF) (Mattei et al., 2010), whereas DPP-8 (PDB:
6HP8) (Ross, 2019) and DPP-9 (PDB: 6EOR) include no bound ligands
(Ross et al., 2018). Potential hit compounds should exhibit a predictive
inhibitory activity against DPP-4 greater than or equal to that of the
original ligands. In contrast, to exhibit nonselectivity for DPP-8 and
DPP-9, hit compounds should have a low inhibitory activity (>10
000 nM) (Huan et al., 2015). Molecular docking was performed using
Autodock (v.1.5.6; Discovery Studio R2 Client 2017; Biovia, San Diego,
CA, USA), and PyMol (v.2.3.4; Schrödinger, Inc., New York, NY, USA).
Before assessing the screened compounds, the original ligands were used
for docking to establish a reference RMSE. Quality docking was indi­
cated by a root-mean-square deviation of < 2 Å. All redocking values
satisfy this threshold.
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Computational Biology and Chemistry 95 (2021) 107597
Fig. 4. Internal validation results using the regression model. Support vector
regression produced the best performance among other models according to the
lowest MSE.
3. Results and Discussion
Dataset diversity is a critical factor when using QSAR methods.
Previous applications of QSAR to assess DPP-4 inhibitors mainly focused
on local (conventional) QSAR modeling using both two- and three-
dimensional QSAR and pharmacophores. However, this provides reli­
able predictions across only a limited chemical space. Therefore, there is
a need to use a more extensive and diverse dataset to build a global
QSAR method (Shi et al., 2018).
3.1. Analysis of the chemical space
For the regression model (Fig. 2A), we used a training dataset with 2
831 molecules with molecular activities ranging from 0.064 nM (pIC50
O. Hermansyah et al. Computational Biology and Chemistry 95 (2021) 107597

Table 1
Internal validation results for the classification model.
Models TP FP TN FN Sensitivity Specificity F-Measure Precision Accuracy

Deep learning 891 93 75 0.9224 0.8942 0.9138 0.9055 0.9079

786
Random forest 925 105 41 0.9576 0.8805 0.9269 0.8981 0.9209
774
SVM 952 457 14 0.9855 0.4801 0.8017 0.6757 0.7447
422
XGBoost 907 93 59 0.9389 0.8942 0.9227 0.9070 0.9176
786

TP = true positive; FP = false positive; TN = true negative; FN = false negative.

Table 2
Statistical parameters for external validation of various models.
Metric DL XGBoost MLR RF SVR Standard

Q2 0.6920 0.7530 0.5939 0.7532 0.7607 > 0.5a

R2(pred) 0.5910 0.7617 0.6013 0.7668 0.7761 > 0.6a
MSE (validation) 0.7686 0.6163 1.0134 0.6157 0.5971 –
MSE (ext) 1.0370 0.6043 1.0109 0.5914 0.5679 –
R20 0.2564 0.6914 0.4597 0.6319 0.7281 –

R′ 20 0.5911 0.7618 0.6014 0.7668 0.7762 –

(R2 − R20 ) / R2 0.5672 0.0924 0.2422 0.1847 0.0624 < 0.1a

(R −2
R′ 20 )
/ R2 0.0023 0.0000 0.0086 0.0107 0.0006 < 0.1a
⃒ 2 ⃒
⃒R − R′ 2 ⃒
0 0
0.3347 0.0704 0.1417 0.1349 0.0481 < 0.3a
k 0.9979 1.0024 0.9976 1.0005 0.9975 0.85 ≤ k ≤ 1.15a
k′ 0.9797 0.9845 0.9805 0.9867 0.9902 0.85 ≤ k′ ≤ 1.15a
R2m 0.2760 0.5181 0.3665 0.4272 0.5668 –

R′ 2m 0.5686 0.7618 0.5586 0.6874 0.7563 –

R2m 0.4223 0.6400 0.4625 0.5573 0.6616 > 0.5b

∆R2m 0.2925 0.2437 0.1920 0.2602 0.1895 < 0.2b

Model Predictive Fail Fail Fail Fail Yes
a
= standard Golbraikh and Tropsha (2002)
b
= standard Roy, Kar & Das (2015)

Table 3
External validation of the classification model.
Models TP FP TN FN Sensitivity Specificity F-measure Precision Accuracy

Deep learning 215 25 10 0.9556 0.8945 0.8958 0.9242

212 0.9247
Random forest 219 29 6 0.9733 0.8776 0.8831 0.9242
208 0.9260
SVM 221 137 4 0.9822 0.4219 0.6173 0.6948
100 0.7581
XGBoost 215 26 10 0.9556 0.8903 0.8921 0.9221
211 0.9227

TP = true positive; FP = false positive; TN = true negative; FN = false negative.

= 10.19) to 9 100 µM (pIC50 = 2.04) and a test set of 787 molecules (for
external validation) with molecular activities ranging from 0.012 nM
(pIC50 = 10.92) to 1 000 µM (pIC50 = 3).
For the classification model (Fig. 2B), we used a training set of 1 845
molecules (879 active and 976 inactive), whereas the test set (external
validation) contained 462 molecules (237 active and 135 inactive).
Analysis of the chemical space was performed to examine the diversity
of the datasets. Fig. 2 shows plots of DPP-4-inhibitor compound diversity
in each dataset according to molecular weight (MW) and partition co­
efficient (XLogP). The results identified that compounds with a MW
ranging from 128.094 Da to 1 173.69 Da and a partition coefficient
ranging from − 4.107–18.493, suggesting that the model demonstrated
significant heterogeneity in the chemical space, potentially resulting in
broader predictive ability for new compounds (Kong and Yan, 2017).
3.2. Feature selection
Feature selection was performed for seven feature types (Fig. 3) to
identify the most optimal feature for use in compound identification,
with this undertaken using the random forest algorithm. This process
reduced 17 569 total features by 98.8%, resulting in 208 features for the
QSAR regression model and 200 features for the QSAR classification
model.
3.3. Optimization of machine learning algorithms
The model with the lowest error and highest accuracy was obtained
from algorithm parameter optimization by searching for the lowest
random error within a specific parameter range across 100 parameter

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O. Hermansyah et al. Computational Biology and Chemistry 95 (2021) 107597

Fig. 5. ROC curve of the four classification models.

Table 4
Performance of QSAR workflow on various targets.
Target Models Q2 MSE R2 (ext) Dataset Curation Training Validation Test

Beta-1 adrenergic receptor (CHEMBL213) Deep Learning 0.6601 0.4265 0.9134 1508 620 446 496 50
MLR 0.1570 1.0578 -0.2724
Random Forest 0.7349 0.3326 0.6462
SVR 0.7312 0.3373 0.6515
XGBoost 0.7099 0.3641 0.6676
Sigma Opioid receptor (CHEMBL233) Deep Learning 0.6730 0.6113 0.0736 2280 1157 832 925 232
MLR 0.4672 0.9959 0.5693
Random Forest 0.7725 0.4253 0.7318
SVR 0.7543 0.4593 0.7311
XGBoost 0.7453 0.4762 0.7422

values and 100 repetitions. Parameter-optimization results were as fol­
lows: deep learning using two dense layers with a learning rate of 0.01
and 100 neurons (RMSE = 0.8335; batches, 65; epochs, 505); XGBoost
(RMSE = 0.7684; rounds, 1000; maximum depth, 13; and eta, 0.2994);
multiple linear regression (RMSE = 0.9605; offset parameter, 0.23707);
random forest (RMSE = 0.7765; number of models, 109; tree depth, 15);
support vector regression (RMSE = 0.7573; cost parameters, 79; degree,
5).
For optimization of classification methods, the deep learning optimal
parameters on the dense layer were obtained using a rectified linear unit
(ReLU) weight-initiation strategy and a leaky ReLU activation function
(batch size, 15; epochs, 843). The highest accuracies for each algorithm
were 0.9431 (deep learning), 0.9404 (XGBoost; nRounds, 500; max­
Depth, 12), 0.9404 (random forest; nMethod, 216; treeDepth, 21), and
0.6938 (support vector regression; sigma, 0.9662; penalty, 25).
Support vector regression showed the best results, which agree with
previous studies that applied the QSAR model to DPP-4-inhibitor anal­
ysis (Gu et al., 2013; Yang et al., 2013). Additionally, this method is
widely used to manage high-dimensional variables, especially with
small datasets, by mapping and transforming nonlinear data kernels into
high-dimensional features. XGBoost has not been extensively employed
in QSAR modeling because it is new compared to other machine learning
methods, although it shows a faster analytical capability and satisfactory
predictive results (Babajide Mustapha and Saeed, 2016).
The optimization results using the algorithms showed accuracy of up
to 94%, although support vector regression showed an accuracy of only
69%, suggesting that the hyperplane was unable to separate active and
inactive compounds in the classification model. However, ensemble-
based models, such as random forest and XGBoost, were able to pre­
dict active and inactive compounds well. These results contrasted with
those of the regression QSAR model, which showed support vector
regression as the best algorithm. In the regression method, the trans­
formation of the variable to higher dimensions resulted in better pre­
diction of pIC50 relative to other methods.
In the regression model, the goodness-of-fit from multiple linear
regression and deep learning were low relative to results from support
vector regression and ensemble methods. This is likely because multiple
linear regressions are intended for linear data and show worse

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O. Hermansyah et al.
Fig. 6. Molecular structures of hit compounds identified by virtual screening.
performance with nonlinear data. For deep learning, the poor results
were likely due to the lack of training data, which hindered model
performance.
3.4. Internal validation
Internal validation of the regression QSAR model showed < 25%
difference for the results derived from all of the models, suggesting no
overfitting (Veerasamy et al., 2011). Support vector regression showed
lowest error (Fig. 4), followed by XGBoost and random forest. Internal
validation of the QSAR classification models (Table 1) revealed that
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Computational Biology and Chemistry 95 (2021) 107597
deep learning, XGBoost, and random forest showed excellent perfor­
mance (accuracy >90%), with random forest showing the best
performance.
3.5. External validation
Although the QSAR regression models met the requirements for pa­
rameters k and k′ , the R20 values for deep learning, multiple linear
regression, and random forest were > 0.1, indicating that they were
unsuitable as predictive QSAR models.
For verification of similarities between observed and predicted data,
O. Hermansyah et al.
Fig. 7. The interaction of compounds CH0001 CH0002 and CH0003 with DPP4. Ojeda-Montes et al. (2018) report that compounds selected for DPP8 and DPP9 have
hydrophobic interactions with Phe357, Arg358, or Tyr547 residues of DPP4. (a) Hydrophobic interaction of the Pi-Pi T-Shaped type between the aromatic group of
the molecule CH0001 and DPP4 (3KWF) at residues Phe357 and Tyr547. (b) Hydrophobic interaction of the Pi-Pi Stacked type between the aromatic group molecule
CH0002 and DPP4 (4PNZ) at residue Phe357. (c) There was no hydrophobic interaction between CH0003 and DPP4 (2ONC) with Phe357, Arg358, or
Tyr547 residues.
Table 2 shows that deep learning and multiple linear regression did not
meet the R2m requirements (values <0.5), whereas the other methods
were eligible, whereas on support vector regression showed an ∆R2m
parameter making it eligible for the QSAR regression model.
Support vector regression fulfilled all requirements necessary for the
QSAR regression model, suggesting that it can be used to predict hit
compounds during virtual screening. Additionally, support vector
regression showed a significant difference between the curves formed by
predictive values and the zero intercept, suggesting increased model
accuracy.
Table 3 shows external validation results of the classification
method, and Fig. 5 shows ROC analysis of the accuracies of the deep
learning, XGBoost, and random forest methods [all higher than previous
studies (accuracy > 80%)] (Cai et al., 2017). Deep learning and XGBoost
algorithms showed better performance on external validation; however,
we used the random forest algorithm to build the virtual screening
workflow based its higher accuracy relative to the other algorithms.
3.6. Testing QSAR regression workflow on other targets
QSAR prediction of several targets (Table 4) produced results with a
coefficient of determination reaching 0.7 for the support vector regres­
sion, XGBoost, and random forest models, suggesting the ability of the
workflow to identify targets from raw datasets downloaded from the
ChEMBL database.
3.7. Virtual screening results
Virtual screening results of the ChEMBL, PubChem, and Molport
databases identified several hit compounds (Fig. 6), which were
compared the DPP-4-inhibitors from the ChEMBL database (similarity
values < 0.85) and with DPP-4 DUD-E decoys. We ultimately identified
2 716 potential hit compounds.
8
Computational Biology and Chemistry 95 (2021) 107597
3.8. Molecular docking results
Molecules showing high potential inhibitory activity after docking
with DPP-4 included CH0002, CH0003 and CH0001 (ChEMBL identi­
fiers). Specifically, CH0002 showed slightly higher inhibitory activity to
trelagliptin (PDB: 5KBY), CH0001 showed higher inhibitory activity
than omarigliptin (PDB: 4PNZ) and CH0003 showed higher inhibitory
activity than almost all ligands.
In accordance with the proposal of Ojeda-Montes et al. (2018) to
produce inhibitors that have potential activity against DPP4 and are
selective against DPP8 and DPP9, a compound must have an aromatic
ring so that it can interaction π –π with Phe357, then have a negatively
charged group so that it can interact electrostatically with Arg358 and
have an aromatic ring another to form an additional –π interaction with
Tyr547. Virtual screening hit compounds, CH0001, CH0002 and
CH0003, have various of these groups (Fig. 7). DPP4 inhibitors such as
trelagliptin, alogliptin, omarigliptin, and carmegliptin also interact with
these residues. In compound CH0003, the interaction with DPP4 (2ONC)
did not form a molecular bond with the residue, which resulted in low
selectivity with DPP8 and DPP9 (Ojeda-montes et al., 2018).
Generally compounds that have inhibitory potential (Ki < 1 µM),
moderate (1 µM < Ki < 10 µM), and weak (Ki > 10 µM) (Havale and Pal,
2009; Kang et al., 2014; Taur et al., 2012). Molecular docking results
using DPP-8 indicated that CH0003 (Ki = 52.98 nM) and CH0001
(Ki = 310.16 nM) showed high potential inhibitory activity and that
CH0002 (Ki = 1190 nM) showed moderate inhibitory activity, which
was similar to trelagliptin (Ki = 1410 nM). For DPP-9, CH0003 (Ki =
22.27 nM) and CH0001 (Ki = 332.85 nM) showed high inhibitory ac­
tivity, whereas CH0002 (Ki = 1220 nM) showed moderate inhibitory
activity, which was similar to carmegliptin (Ki = 1730 nM). As the result
of molecular docking of hit compounds against DPP4, DPP8 and DPP9
(Table 5), the best compound from the virtual screening study was
CH0002 (Fig. 8), which showed potential inhibitory activity against
DPP4, but moderate inhibition against both DPP8 and DPP9. The
O. Hermansyah et al. Computational Biology and Chemistry 95 (2021) 107597

Table 5
Molecular docking results of hit compounds with DPP-4, DPP-8, and DPP-9.
Macromolecule Ligand Binding Inhib_Constant Molecule
(PDB ID) Energy (Ki)
Kcal/mol nM

DPP4 (5KBY) 6RL1510 − 9.66 82.49 Trelagliptin

CH0001 − 9.42 125.21
CH0002 − 9.67 81.13
CH0003 − 11.27 5.51
MP0001 − 5.67 69420
MP0002 − 8.54 551.45
MP0005 − 4.55 459580
PC0001 − 6.68 12780
PC0002 − 7.13 5910
PC0003 − 8.43 658
DPP4 (2ONC) SY1800 − 10.43 22.83 Native Ligand
of 2ONC
CH0001 − 9.51 106.54
CH0002 − 9.78 67.62
CH0003 − 11.46 4
MP0001 − 5.27 136760
MP0002 − 8.5 586.04
MP0005 − 4.7 358230
PC0001 − 6.43 19500
PC0002 − 6.77 10940
Fig. 8. Visualization of the CH0002 hit compound with DPP-4 (PDB: 4PNZ).
PC0003 − 7.97 1440
DPP4 (4PNZ) 2VH802 − 10.37 25.12 Omarigliptin
CH0001 − 9.78 67.96 compound CH0001 had a higher inhibitory activity against DPP8 and
CH0002 − 8.22 940.40 DPP9 than CH0002, while CH0003 had the lowest selectivity.
CH0003 − 8.91 293.62
MP0001 − 4.89 261080
MP0002 − 7 7420 4. Conclusions
MP0005 − 3.69 1980000
PC0001 − 6.86 9350 In summary, we developed a QSAR method that uses AI to create a
PC0002 − 6.65 13280
PC0003 − 7.66 2410
virtual screening workflow that meets QSAR statistical parameter
DPP4 (3KWF) B1Q1 − 9.75 71.41 Carmegliptin standards. Additionally, we identified support vector regression as the
CH0001 − 9.05 234.16 best algorithm for satisfying QSAR parameters, resulting in > 90% ac­
CH0002 − 9.21 177.65 curacy in the classification model, with ROC curve of 0.96. The optimal
CH0003 − 10.11 39.1
algorithm for classification method was random forest, which was used
MP0001 − 4.04 1090000
MP0002 − 7.41 3730 to predict hit compounds, with support vector regression used to predict
MP0005 − 4.16 897610 their activity. Virtual screening identified 2 716 compounds, which were
PC0001 − 6.94 8170 then analyzed by molecular docking with DPP-4, DPP-8, and DPP-9,
PC0002 − 6.35 22310 revealing CH0002 as a selective inhibitor of DPP-4.
PC0003 − 7.59 2720
DPP8 (6HP8) GK2901 − 6.69 12490 Native ligand
Declarations.
of 6HP8
CH0001 − 8.88 310.16 Ethics approval and consent to participate
CH0002 − 8.08 1190
CH0003 − 9.93 52.98
MP0001 − 6.42 19660
Not applicable.
MP0002 − 5.88 48820
MP0005 − 4.17 879860 Funding
PC0001 − 6.91 8650
PC0002 − 6.22 27410
PC0003 − 7.4 3790
This work was supported by the fund through PITTA Indonesia (In­
2VH802 − 5.21 152160 Omarigliptin ternational Indexed Publication for UI Student Final Project) 2019 grant
B1Q1 − 6.26 25890 Carmegliptin (NKB-0472/UN2. R3.1/HKP.05.00/2019) awarded to A.Y. from the
6RL1510 − 7.98 1410 Trelagliptin Directorate of Research and Community Service at the University of
SY1800 8.54 551 Native ligand
Indonesia for publication manuscript.
−
of 2ONC
DPP9 (6EOR) 9XH901 − 11.24 5.8 Native ligand
of 6EOR CRediT authorship contribution statement
CH0001 − 8.84 332.85
CH0002 − 8.07 1220
OH designed the study, implemented all KNIME workflow develop­
CH0003 − 10.44 22.27
MP0001 − 5.28 135300 ment, and prepared the manuscript; AB helped with study design; AY
MP0002 − 7.11 6130 supervised the study; OH, AB, and AY discussed the results; OH and AY
MP0005 − 4.37 630360 analyzed data and wrote the manuscript; and all authors read and
PC0001 − 7.23 5000 approved the final manuscript.
PC0002 − 6.82 10060
PC0003 − 7.76 2050
CH0090 − 8.28 857.76 Declaration of Competing Interest
2VH802 − 8.32 792 Omarigliptin
B1Q1 − 7.86 1730 Carmegliptin
6RL1510 − 7.42 3660 Trelagliptin The authors declare that they have no known competing financial
SY1800 − 7.34 4150 Native ligand interests or personal relationships that could have appeared to influence
of 2ONC the work reported in this paper.

9
O. Hermansyah et al. Computational Biology and Chemistry 95 (2021) 107597

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