Briefings in Bioinformatics, 2023, 24(3), 1–27

https://doi.org/10.1093/bib/bbad120
Advance access publication date 6 April 2023
Review

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Machine learning for synergistic network pharmacology:
a comprehensive overview
Fatima Noor† , Muhammad Asif† , Usman Ali Ashfaq, Muhammad Qasim and Muhammad Tahir ul Qamar
Corresponding author. Muhammad T. u. Qamar, Department of Bioinformatics and Biotechnology, Government College University, Faisalabad 38000, Pakistan.
E-mail: tahirulqamar@gcuf.edu.pk
† F. Noor and M. Asif contributed equally.

Abstract
Network pharmacology is an emerging area of systematic drug research that attempts to understand drug actions and interactions
with multiple targets. Network pharmacology has changed the paradigm from ‘one-target one-drug’ to highly potent ‘multi-target
drug’. Despite that, this synergistic approach is currently facing many challenges particularly mining effective information such as drug
targets, mechanism of action, and drug and organism interaction from massive, heterogeneous data. To overcome bottlenecks in multi-
target drug discovery, computational algorithms are highly welcomed by scientific community. Machine learning (ML) and especially
its subfield deep learning (DL) have seen impressive advances. Techniques developed within these fields are now able to analyze and
learn from huge amounts of data in disparate formats. In terms of network pharmacology, ML can improve discovery and decision
making from big data. Opportunities to apply ML occur in all stages of network pharmacology research. Examples include screening
of biologically active small molecules, target identification, metabolic pathways identification, protein–protein interaction network
analysis, hub gene analysis and finding binding affinity between compounds and target proteins. This review summarizes the premier
algorithmic concepts of ML in network pharmacology and forecasts future opportunities, potential applications as well as several
remaining challenges of implementing ML in network pharmacology. To our knowledge, this study provides the first comprehensive
assessment of ML approaches in network pharmacology, and we hope that it encourages additional efforts toward the development
and acceptance of network pharmacology in the pharmaceutical industry.

Keywords: network pharmacology, artificial intelligence, machine learning, deep learning, drug discovery

BACKGROUND [4–6]. Multi-target drugs have gained considerable interest in the

Drug discovery and development together is the whole pro-
cess of identifying novel and effective drug candidates and
considered as a key part of clinical pharmacology [1]. Drug
discovery involves many different processes including screening
of chemical libraries and identification of biologically active
small molecules [2]. On the other hand, drug development
includes optimization of small molecules, toxicological studies
on different microorganisms and animals, clinical trials and
ultimately regulatory approval [3]. Over the last decade, the
‘one disease–one target–one drug’ paradigm has dominated the
drug discovery approaches. However, this paradigm has several
limitations and recent advancements in systems biology has
shifted the focus from ‘single-drug target’ to ‘multi-target drugs’
last decade because of their potential to treat diseases involving
interaction of multiple genes, thus yielding successful outcome
as compared to single-target drugs [7].
Network graphs provide a convenient conceptual framework
for systems-level modeling, integrating and mining of high-
throughput experimental datasets. This helps in understanding
and gaining insights into different types of molecular relationship,
such as how genes are linked to various diseases or interactions
between drugs and their cellular targets [8]. Systems or network
biology has proven useful for deciphering fundamental research
questions, such as how perturbations in the cellular networks
lead to certain phenotypes, including human diseases [9, 10].
In network context, the efficacy of multi-target therapy can be

Fatima Noor is currently an MS Bioinformatics scholar at the Integrative OMICS & Molecular Modeling Lab, Department of Bioinformatics and Biotechnology,
Government College University Faisalabad, Pakistan. Her current research focuses on the development of machine learning-based tools for integrated biomedical
data analysis.
Muhammad Asif is an Assistant Professor at the Department of Bioinformatics and Biotechnology, Government College University Faisalabad, Pakistan. He has
PhD in Systems Biology and Bioinformatics. He is leading a biomedical data analysis lab, where he is mainly focused on developing machine and deep learning
methods/software for biomedical data integration and analysis, in particular for bulk sequencing, and single-cell omics.
Usman Ali Ashfaq is a Professor at the Department of Bioinformatics and Biotechnology, Government College University Faisalabad, Pakistan. He is leading a
health biotechnology lab, where he is mainly focused on the diagnosis and treatment of in fectious and metabolic diseases using advanced Bioinformatics
approaches.
Muhammad Qasim is a Professor and currently serving as the Chairperson of the Department of Bioinformatics and Biotechnology, Government College
University Faisalabad, Pakistan. His research interests include high-throughput genome sequencing data analysis, genomic medicine, and integrated
Bioinformatics.
Muhammad Tahir ul Qamar is an Assistant Professor and leading Integrative OMICS & Molecular Modeling Lab at the Department of Bioinformatics and
Biotechnology, Government College University Faisalabad, Pakistan. He received his Ph.D. degree in Bioinformatics from Huazhong Agricultural University, Wuhan,
China. His research focuses on developing methods, resources, and software for bulk/single-cell sequencing data analysis, with a particular focus on
Pan-genomics.
Received: August 2, 2022. Revised: March 5, 2023. Accepted: March 10, 2023
© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com
2 | Noor et al.

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Figure 1. Workf low representing the network pharmacology research to decipher the biologically active molecules for the treatment of incurable
diseases. At first, it analyzes the targets from different resources including experimental data, public data available in databases, and then performs
network analysis. Based on integrative analysis, it identified hub genes specifically involves in the dysregulation of pathway that leads to disease
condition. Finally, it performs experimental and computational validations.

understood from a robustness of disease networks to deal with
single node perturbations, due to inherent diversity and redun-
dancy of compensatory signaling pathways that result in highly
resilient network architecture with modular and interconnected
topology. Therefore, network-based drug discovery seeks for drug
target combinations to perturb a specific subset of nodes in the
disease-associated networks to inhibit the bypass mechanisms
at systems level [11]. These recent developments have resulted
in moving away from the traditional ‘one target’ strategy toward
network pharmacology [12].
Network pharmacology is recent frontier in systematic drug
research as it tends to elucidate the drug actions as well as
their interaction with multiple targets [13]. This approach is
combining, experimental, computational and clinical advances
to increase the clinical efficacy of drugs [14]. It has now
been dubbed as ‘next paradigm in drug development’ as it
presents a comprehensive grasp of systems biology with network
theories [15]. This systematic approach revolves around the
identification of synergistic and mechanistically related co-
targets of active compounds in a network perspective (Figure 1)
[16]. Synergistic is a multi-objective approach where synergy
can be observed from a network pharmacology perspective.
Synergistic describes the interaction of two or more compounds
when their combined effect is greater than their individual effect
[17]. Synergistic activity may emerge from a set of targeted
proteins, related mechanisms, or compounds combinations.
In network pharmacology, synergistic action is due to the
combinatorial effects of active compounds on multiple targets
identified by network topological features [18, 19]. Network
pharmacology aims to understand ‘network-target, multiple-
component-therapeutics’ by ‘compound-protein/gene-disease’
network revealing the regulation principles of small molecules
in a high-throughput manner and analysis of drug combinations,
hence synergy.
Identification of disease and compound-related target is a
preliminary step to figure out the anti-disease-related compound
targets [20, 21]. Following that, the protein–protein interaction
(PPI) network of target proteins is constructed, analyzed and
visualized to get a better understanding of the proper function-
ing of molecular mechanisms perturbed in disease states [21].
Later, it extracted hub genes on the basis of their degree of
connective from gene networks. Finally, further network valida-
tion is carried out to evaluate the interaction between active
compounds and their potential disease targets [22, 23]. In sum-
mary, network pharmacology can assist in evaluating the effi-
ciency of multi-component, multi-target compound formulas and

exploring more therapeutic strategies by targeting a specific net-
work. Despite that, this approach is facing challenges including
limited technological advancements and knowledge to identify
novel drug targets, lack of synergistic drugs and poor quality of
databases in terms of data management [24, 25]. To bridge the gap,
computational algorithms must be exploited to overcome the
limitations of network pharmacology.
Machine learning (ML) approaches are becoming popular
across all facets of sciences. Fundamentally, ML is the practice of
using algorithms to parse data, learn from it and then accordingly
make a prediction about the future state of any new dataset [26,
27]. In ML data and algorithms like K-Nearest Neighbors (kNN),
Decision Tree, Support Vector Machine (SVM), Naïve Bayes and
Hidden Markov Model (HMM) are used to imitate the way how
humans learn [28, 29]. Advancements in ML has paved the road
to the discovery of synergistic drugs [30]. Big data and cutting-
edge algorithms are now readily available, which has increased
interest and led to substantial advancements in the application of
ML in network pharmacology [31]. All pharmaceutical companies
are routinely combining multiple ML algorithms to streamline
the process of discovering new drugs. ML approaches can foster
data-driven decision-making and has the potential to accelerate
the process and decrease the error rates in the drug discovery
process [32, 33]. Ever since its conception, ML has undergone a
half-century of development and has been effectively applied to
a wide range of industrial and technological domains.
ML techniques are increasingly being implemented to deal
with the limitations of network pharmacology process owing
to advancements, globalization and the adaptation of big data
available for producing meaningful insights. The existing reviews
are focused merely on drug–target or drug–drug interaction pre-
diction. The significant research on finding drug interaction with
a network of targets (instead of single target) is missing. Currently,
to the best of our knowledge we do not have any tool or classifier
that could predict the interaction of a drug compound with a
network of targets. The main objective of this review is to cover the
basics of ML methods for network pharmacology that may stim-
ulate new research trends. Our review discusses the application
of ML as a benchmark to advance the multi-target drug discovery
by modernizing network pharmacology research. We also address
crosstalk between different databases/tools used in ML to improve
decision-making and deducing risk failures in multi-target drug
discovery, along with the future of ML approaches in network
pharmacology research. Brief ly, this review article intends to open
new avenues for the discovery of putative treatment options by
combining powerful ML techniques with network pharmacology.
REVOLUTIONIZING THE NETWORK
PHARMACOLOGY: BIG DATA AND ML
Big data is a collection of datasets which are big and complex
to be evaluated by using traditional data analysis software, tools
and procedures [34, 35]. Volume, velocity and variety are the three
fundamental characteristics of big data, wherein volume ref lects
the massive amount and quantity of data generated, velocity
describes the rate at which these data are multiplied, and variety
signifies the heterogeneity found in the huge datasets [36]. Day
after day, a wealth of biological data is generated by virtue of
high throughput technologies such as sequencing technologies,
contributing to the transformation of modern drug development
through network pharmacology into the big data era [37, 38]. Tar-
get prediction is the preliminary step in network pharmacology
pipelines. Now researchers have access to plenty of biomedical
Machine learning for synergistic network pharmacology | 3
data resources that can provide a helping hand in this endeavor
[39]. However, they need advance approaches to smartly process
this available data. The advancements in ML have made big data
analytics significantly must easier, as there is a plethora of ML
approaches that may assist in extracting meaningful features,
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patterns and structures from large biomedical datasets [40]. Guo
et al. [41] proposed an unsupervised ML approach to explore
the cellular functional similarity of XiaoErFuPi granules. They
used hierarchical clustering and then classify the compounds
into several different modules with similar therapeutic functions.
Later, the predicted modules have similar function fingerprints
with various FDA-approved drugs. Thus, the prediction of small
molecules based on the similar function fingerprints proven more
effective as compared to applying simple criteria of drug likeness
and bioavailability. Their study yielded successful outcome by
providing a new insight to the synergistic activity of XiaoErFuPi
granules against dyspepsia.
Synergistic combinations of drugs can overcome toxicity
and other side effects associated with high doses of single
drugs, by either countering biological compensation, sparing
doses on each compound, or accessing context-specific multi-
target mechanisms [42]. The growing availability of large-
scale, high-throughput data has prompted the development
of computational approaches that can effectively predict
the potential synergistic drug combinations. Considering the
limitations of previous computational methods, Li et al. [43]
developed a new model named Siamese Network and Random
Matrix Projection for Anti-Cancer Drug Combination prediction
(SNRMPACDC). Besides, SNRMPACDC achieved the Area under the
ROC Curve (AUC) of 0.91 ± 0.03 and the Area Under the Precision–
Recall curve (AUPR) of 0.62 ± 0.05 in 5-fold cross-validation of
classification prediction of synergistic or not. These results
indicated that SNRMPACDC would be an effective approach
to infer potential anticancer synergistic drug combinations.
Similarly, Chen et al. [44] developed a novel algorithm named
as Network-based Laplacian regularized Least Square Synergistic
drug combination prediction (NLLSS) for prediction of potential
synergistic drug combinations by integrating different kinds of
information including drug–target interactions, drug chemical
structures and known synergistic drug combinations. Compared
with the traditional method of splicing drug features into drug
combination features, these computational models can improve
the interpretability of drug combination features to a certain
extent.
Nowadays, gene expression analysis is frequently used to cap-
ture the pathophysiological mechanisms of diseases as well as to
uncover genes involved in the disease conditions. The technolo-
gies of microarray and RNA-seq has produced a vast quantity of
gene expression data for a variety of diseases. A huge quantity
of gene expression data has been produced with the emergence
of NGS technologies and stored in publicly available databases
such as The Cancer Genome Atlas (TCGA) [45], ArrayExpress [46]
and Gene Expression Omnibus (GEO) [47]. Voluminous data are
produced from these platforms. Regarding this, ML techniques are
warmly welcomed by the scientific community to identify unique
patterns that are relevant to a specific biological problem. Recent
studies imply kNN algorithm on gene expression data for the iden-
tification of prognostic genes underlying the disease condition
[48]. However, unfortunately, we do not have any successful stud-
ies in network pharmacology, where ML assisted gene expression
data is being used for the identification of therapeutic targets. Sev-
eral functionally significant pathways involved in a particular dis-
ease condition are unknown. This information is now expanded
4 | Noor et al.
due to an unprecedented increased in high-throughput data. ML
approaches are widely used by researchers to identify specific
pathways because ML is capable of handling big and complex data
sets. Baranwal et al. [49] applied deep learning (DL) algorithms
for metabolic pathways prediction. They used graph Convolution
Neural Network (CNN) with RF to predict the set of pathways
to which a specific small molecule may belong. At present, the
applications of DL and cloud computing sparked a lot of interest
in network pharmacology, notably in screening bioactive com-
pounds, targets and action pathways of single drugs. Several
studies employed ML or DL to predict either drug–drug or drug–
target interactions. For example, Monteiro et al. [50] employed
CNN to extract a 1D representation from 1D raw data, amino acid
sequence and SMILES. The extracted features representing the
local dependencies were fed to a fully connected neural network.
The proposed DL architecture model resulted in a high sensitivity
(0.861), specificity (0.961) and overall accuracy of 0.923 when com-
pared with the other traditional models. Heba et al. [51] proposed
an ML approach that exploits the both sequence and protein
structural features to predict drug–target interactions. Authors
evaluated the performance of SVM, RF, ensemble and DL tech-
niques in predicting the drug target interaction. Heba et al. found
that ensemble learning methods (Light-Boost and ExtraTree) out-
performed the previously reportedly methods with an accuracy
of 98% and 0.97 F1-score, which is 2% higher average accuracy
than the existing methods. Recently, Zong et al. [52] have also pre-
sented a comprehensive benchmark, called BETA for drug–target
prediction. A large multipartite network, along with different
validation techniques were employed in BETA, which may help in
deciding the computational strategies for drug–target interaction
prediction. Network-based methods along with structure and
sequence-based methods were used for the purpose of evaluating
proposed benchmark based on the input data. Overall, the results
demonstrated that in general, the best methods for network-
based and structure- and sequence-based methods are DeepPur-
pose (CNN) [53] (average AUCROC: 88.01%, PRAUC: 84.44%, preci-
sion: 73.40%, recall: 86.73%, F1: 79.49%, general score: 83.98%) and
NeoDTI [54] (average AUCROC: 86.52%, PRAUC: 83.32%, precision:
71.40%, recall: 80.78%, F1: 74.19%). It, in a sense, represented an
indirect connection between topology-, structure- and sequence-
based features for drugs and proteins in drug development con-
texts.
Despite these efforts, new tools with ability to predict drug
interaction with a network of targets are required. In this review,
along with network pharmacology we have discussed highly
sophisticated ML and DL methods. The main objective was to
stress on surging interests in network pharmacology that may
stimulate new research trends.
ML METHODS FOR IMPROVING
MULTI-TARGET DRUG DISCOVERY IN
NETWORK PHARMACOLOGY
The advent of ML techniques was first unveiled in 1950 and has
already been employed in modern fields including bioinformatics,
systems biology, network pharmacology and many others [55].
Particularly, ML approaches can be applied in five main steps for
multi-target drug discovery (Figure 2) including (i) data collection,
(ii) retrieving different types of molecular descriptors, (iii) figure
out optimal subset of variables, (iv) Training of model and (v)
validation of trained model [56, 57]. At first, it collects infor-
mation about small biologically active molecules from different
resources. Data collection is extremely important. The quality
and quantity of data determine the effectiveness of final predic-
tive model. Following that, it generates different types of robust
mathematical descriptors to predict the toxicity and bioactivity
of molecules from their structure. For analysis, the model is
trained with training datasets to analyze how it respond to data
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which it evaluate/seen before. Lastly, model testing is carried out
to validate the raw data and to evaluate the performance of
predictive model [56, 58]. Altogether, this workf low provides the
base for multi-target drug discovery.
ML is less obsessed with hypothetical breakthroughs and more
focused on translating medical data into studies that can be
reused. Nowadays, countless ML approaches are used in network
pharmacology to analyze the drug action (Figure 3), including
Autoencoder (AE), HMM, Multi-Layer Perceptron (MLP), RF, SVM,
kNN and more important DL to improve decision making in net-
work pharmacology. AE is a subtype of Artificial Neural Network
(ANN) where neural network is trained to reconstruct the input
in an unsupervised manner. AE is highly capable of spotting
fundamental structure of input data rather than memorizing
them [59, 60]. AE has a key role to play in the discovery of small
molecule as drug candidate against incurable diseases. Recently,
Hu et al. [61] used fully connected neural networks to construct
drug-likeness classification models with deep AE to initialize
model parameters. Their study provided a 91.04% classification
accuracy of drug-like/nondrug–like models 91.04% on World Drug
Index (WDI)/Available Chemicals Directory (ACD) databases while
91.20% classification accuracy of drug-like/nondrug–like models
on MACCS-II Drug Data Report (MDDR)-ZINC database. Following
that, Emdadi et al. [62] introduced Auto-HMM-LMF, a novel and an
efficient feature-selection method used by researchers to predict
the response of specific drug. Auto-HMM-LMF used HMM and AE
for feature selection. HMM is a general modeling technique used
in unsupervised learning for the modeling of biological sequences
[63]. A combination of HMM with AE assists the researcher to
analyze the properties of active compounds. However, no study
to date used AE and HMM for multi-target drug discovery in a
network pharmacology perspective. Therefore, the prediction of
drug-likeness properties of compounds and action mechanism of
active compounds using AE and HMM might help in the screening
of potential active compounds for further analysis. A few common
models, including as SVM, RF and DL, are described in detail in
order to promote multi-target drug discovery by combining ML
approaches with network pharmacology.
Support Vector Machines
SVMs are supervised learning methods and can be used for both
classification and regression analysis [64, 65]. SVM creates a n-
dimensional feature space, where n is the number of features.
SVM aims for finding a hyperplane that can classify data into
distinct classes with a minimal error (Figure 4) [66]. The goal of
SVM is to divide the datasets into classes to find a maximum
marginal hyperplane. First, SVM will generate hyperplanes iter-
atively that segregates the classes in best way. Then, it will choose
the hyperplane that separates the classes optimally [67]. SVM can
be liner and non-liner, which can be defined by choosing a kernel.
In SVM, X represented the feature vector, or the input provided
to SVM, whereas Y represents the output or class, i.e. Y ∈ {−1, 1}.
At the same moment, X ∈ Rn , where n is a dimension feature
vector. The subject of classifying binary class is explored here.
Parameters in SVM w and b have considered for learning data
in training set. w is normal to the line and known as the weight
vector, whereas b is the bias. The main goal of the learning data
is to find the optimal set of weights, which can ideally produce
 Machine learning for synergistic network pharmacology | 5

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Figure 2. Workf low of ML methodology to improve the multi-target drug discovery process. At first, it collected data and then generate mathematical
descriptors to place corresponding patches close to each other. Later, it trained the model and then cross-validate the model.

the correct output for the relative input. Xi and are the ith sam- Similarly,
ple in the dataset, whereas the f (X) can also be represented as
follows: 2  
minw = Yi wT Xi + b ≥ 1 for i = 1, 2, 3, .., N (3.4)
 ||w||
≥ 0 Yi = 1
f (Xi ) = (3.1)
< 0 Yi = −1
It then generates a quadratic optimization model, such as
  minw
 
The output can be described as f (Xi ) Y(i) + b ≥ 1. Obtain a w,b2
.therebyY(i) wT Xi + b ≥ 1, for i = 1, 2, 3, .., N.
weight vector w such that the discriminant function is satisfied Because the above-mentioned equation was indeed a hard
with the linearly separable data Xi labeled into two classesYi = margin SVM, we can overcome this issue by using the linearly
{−1, 1}: separable technique. Simply use slack variables as constraints.
Each sample in the training data has its own slack variable.
f (Xi ) = wT Xi + b (3.2) Therefore,

min ||w|| N
+C (3.5)
It separates the categories for i = 1, 2, 3, ..N. The distance w, b2 ∈i
i
between two hyperplanes wT X + b = −1 and wT X + b = 1should  T 
maximized the separation between two endpoints. As a result, Yi w Xi + b ≥ 1 − ∈i for i = 1 2, 3, . . . , N (3.6)
2
Distance = maxw ||w|| 2
. Later, it solves the maxw ||w|| minw ||w||
2
:
where C is a regularization parameter. C parameter adds a penalty
2 ≥1 if Y =+1 for each misclassified data point. For large values of C, the
maxw = wT Xi + b≤−1 if iY =−1 for i = 1, 2, 3..N (3.3)
||w|| i
optimization will choose a smaller-margin hyperplane if that
6 | Noor et al.

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Figure 3. Overview of ML tools and techniques for multi-target drug discovery. Unsupervised techniques are used to construct models that enable data
clustering, whereas supervised learning techniques including regression and classifier approaches are used to solve queries that demand the prediction
of data categories or continuous variables. Thus, both provide a helping hand in network pharmacology research.

hyperplane does a better job of getting all the training points
classified correctly. Conversely, a very small value of C will
cause the optimizer to look for a larger-margin separating
hyperplane, even if that hyperplane misclassifies more points.
Adding a function ∅ in order to provide additional mapping
f lexibility. Consequently, it translates diverse characteristics
such as original space to high-dimensional space. The updated
equation is
 
Thus, Yi wT φ Xi + b ≥ 1 − ∈i for i = 1, 2, 3, . . . , N
The SVM, with its kernels, is frequently employed in net-
work pharmacology to identify effective compounds against com-
plex diseases. Dai et al. [68] used network pharmacology-based
approach for the identification of traditional Chinese medicinal
formula against Huntington’s disease. Later, they used SVM to
validate their findings. To construct well-trained Quantitative
Structure–Activity Relationship (QSAR) models they applied SVM
algorithms on generated descriptors. Their study combines ML-
algorithms with network pharmacology which lays a new sci-
(3.7) entific foundation to analyze the efficacy of small molecules
 Machine learning for synergistic network pharmacology | 7

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Figure 4. Operational workf low of SVM.

for exploring more multi-target drugs in future. Furthermore, consists of M = M1 , M2 , . . . , Mn , N = N1 , N2 , . . . , Nn :

Zernov et al. [69] used SVM to predict the drug-likeness of small
molecules. It is worth noting that SVM model used for prediction ⎡ ⎤
M1 N1
of drug-likeness property of small molecules is much better than
⎢ M2 N2 ⎥
using traditional QSAR. Lei et al. [70] used SVM to predict the oral ⎢ ⎥
⎢ ⎥
⎢ M3 N3 ⎥
acute toxicity in mammals. However, currently in network phar- P= ⎢ ⎥ (3.8)
⎢ . . ⎥
macology no study to date implementing SVM algorithm to access ⎢ ⎥
⎣ . . ⎦
the drug-likeness and toxicity of small molecules. Therefore, SVM
Mn Nn
algorithms can be used in network pharmacology to predict the
efficacy of active compounds.

where M1 represents the feature of first sample, N1 represents

the features of second sample, whereas n represents the infinite
Random Forest
features. Thus, the main objective is to create an RF by classifying
Random Forest (RF) is a powerful and versatile supervised
the sample set i.e., P. Following the sample set P, a list of subsets
ML algorithm that grows and combines multiple decorrelated
is created with random values.
decision trees to create a ‘forest’. It uses bagging and feature
Alternate samples with n trained examples from M, N then Ma ,
randomness when building each individual tree to try to create
Na . To make a prediction at a new point i.e.,  o to bth RF tree:
an uncorrelated forest of trees whose prediction is more accurate
than that of any individual tree [71]. Over-fitting can emerge in
regression and classification tasks, which may consequent into 1 B
f̂ = fb (o) (3.9)
a biased classifier. The chances of over-fitting may be reduced B b=1

for some datasets by applying RF algorithm. RF revolves around

the implementation of trained algorithms approaches such as
bagging [72]. The main theme of bagging method is that the
combination of learning models improves the final output.
Generally, the datasets consist of a matrix of trained samples
for the construction of a classification model. The trained sample
A simple majority can be used in classification trees. Lastly,
because there is no more incremental bias in the RF model, it
generates superior results and lowers variation in the model.
Therefore, the standard deviation form of the equation for an
8 | Noor et al.
Figure 5. The RF constructed a visual decision tree to retrieve calculations
for each sample and then vote on the best outcomes. It first test the sam-
ple input and then average all predictions. Based on the voting/averaging
final prediction is made [Figure is adopted/modified from Dara et Al. [72]
© (2021) Springer].
independent regression tree on x is
B  2
 b=1 fb (o) − f̂
Standard deviation = (3.10)
B−1
where B is an arbitrary parameter. The RF algorithm integrates
many different decision trees by using ensemble learning [73],
a method for solving complicated problems by combining a
set of classifiers (Figure 5). In network pharmacology, especially
for validation of interaction between the active molecules and
target proteins, the RF algorithm can improve the performance
of the scoring function. Chen et al. [74] combine the RF
method with network pharmacology to predict the bioactivity
of natural compounds against Alzheimer disease. RF algorithms
build different models for calculating the possibility of natural
compounds as a treatment option for Alzheimer’s disease.
Their findings proposed that Cynanogenin A and Methyl 3-O-
feruloylquinate has strong binding affinity with target protein
(Glycogen synthase kinase-3β). Thus, these compounds can be
used for the treatment of Alzheimer’s disease. Wu et al. [75] used
network pharmacology-based approach to analyze the synergistic
activity of Aconiti Lateralis Radix Praeparata. The authors used RF
method and built the target prediction model, which revealed that
22 compounds have multi-target effect and can be an efficient
candidate against incurable diseases. Similarly, Chen et al. [76]
used RF to predict the compound–target interactions from multi-
molecular network. Naorem et al. [77] used RF for the selection
of hub genes from pool of differentially expressed genes. After
selection, different classification models were generated using
RF that confirm that the hub genes might act as biomarker
and therefore easily differentiate triple-negative breast cancer
from non-triple-negative breast cancer. Similar studies in future
can boost the multi-target drug discovery which in turns will
provide effective treatment option against complex diseases and
disorders.
Deep learning
DL is a subtype of ML and is neural networks make up the
backbone of DL algorithms, which can retrieve a higher level
of information from input data by stacking numerous layers
together [78]. The operational workf low of DL algorithm consists
of six main steps (Figure 6): (i) data retrivel – data are retrieved
from different resources; (ii) feature extraction – where it translate
the data into useful features; (iii) data partitioning– where it is
divided into training, testing and validation sets; (iv) developing
deep architecture and training it; (v) the performance of traiend
model is evaluated; and, lastly (vi), deployment of the model. DL
algorithms has recently been employed in a variety of scientific
domains. DL has a neural network architecture that comprises a
set of layers and allows input to be processed between them [79].
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DL models make use of many different algorithms. Each algorithm
has its own pros and cons and is well suited for a specialized task.
Therefore, it is necessary to develop a thorough understanding
of all DL algorithms for achieving better results. MLPs, Convolu-
tional Neural Networks (CNNs), Deep Neural Networks (DNNs)
and Recurrent Neural Networks (RNNs) are extensively used by
researchers for drug discovery which are described below.
The MLP model is a fully connected class of feedforward
ANN. ANN is an interconnected group of nodes that mimics
the way nerve cells work in the human brain. MLP generates
output depending on a set of input data [80]. MLP composed
of interconnected neurons transferring information from one
neuron/layer to another just like in brain. A single neuron in this
network is called perceptron. Each perceptron in MLP accepted n
features from input layers (a = a1 , a2 , a3 , . . . an ). All these features
are interconnected with some specific weights. The input features
are then passed to a new non-linear function (z) which mainly
aims to predict the weights for all input features simultaneously:

n
z(a) = wi ai (3.11)
i=1
Further, the result of z function is transferred to activation
function ∅ and output of a particular perceptron is reached:

if z(a) > θ then, 1
Output = φ (z(a)) = (3.12)
else, 0
where θ represents a threshold parameter. Equation (3.12) esti-
mates that whether w1 a1 , w2 a2 + w3 a3 + . . . wn an − θ > 0 is a false
condition or a true condition.
The architecture of MLP is composed of three layers (Figure 7):
(i) input layer passes input features to the hidden layer; (ii) hidden
layers may be one or more than one in MLP. The first hidden layer
gets input features from the input layer. The first hidden layer
then passes the output of the perceptron to the second hidden
layer and so on. (iii) There is only one output layer that receives
each perceptron of the previous hidden layer as an input. Where
is the final node in the output layer? If the weights in a hidden
layer are changed, the activation function can change the weights
in the output layer. As a result, it trains optimal weights, and
then input features are boosted with current weights to determine
if a given neuron was aborted or not. Thereby, MLP employs a
back-propagation approach with the activation function. As it
leverages experimental data to estimate the accuracy, therefore,
MLP has one privilege that it does not require specific structural
information. Nowadays, researchers uses MLP to analyze the sta-
bility of particular compound with target proteins [81]. Bustamam
et al. [82] used MLP to evaluate the drug-likeness properties of
compounds. Similarly, Altalib et al. [83] used MLP for similarity-
based virtual screening. The future of MLP is bright, therefore,
they can be proposed to expand the knowledge of compound–
target interactions in network pharmacology. We believe this to
be a robust and relatively versatile model that has the potential
for high generalized predictive accuracy with further tuning.

Figure 6. Simple workf low of DL method.
Figure 7. Architecture of MLP. Architecture of MLP is composed of series of
layers, neurons and their connections. The inputs are forwarded through
the MLP by calculating the dot product of the input and the weights that
exist between the input layer. The hidden layer produces a value from this
dot product. Transfer the estimated output from the hidden layer, then
again calculate the dot product with the associated weights to forward it
to the next level in the MLP [Figure is adopted/modified from Dara et al.
[72] © (2021) Springer].
DNN architecture evolved from an extension of ANN and con-
tains multiple layers between input and output nodes [84]. The
Machine learning for synergistic network pharmacology | 9
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DNN architecture follows the findings of a mathematical model,
which can be both non-linear or linear. Each mathematical model
was intended to be a layer, and in complicated DNN, numerous
layers are available hence, the network was dubbed as ‘deep.’
Multi-task neural networks has incorporated DNN into an integra-
tive platform so called as ‘DeepChem,’ which aids the multi-task
neural networks efficiency in drug discovery and development
[85]. Grebner et al. [86] used DNN to evaluate the bioactivity and
ADME properties of small compounds. Similarly, Chen et al. [87]
used DNN to construct gene regulatory network. Their findings
suggested that the DNN performs better and can efficiently dis-
tinguishes key functional modules between healthy individuals
and individual with coronavirus disease. These studies provide
a realistic picture that DNN can be successfully used for multi-
target discovery in network pharmacology.
A CNN is used to analyze visual images [88]. CNN comprises
of one or more convolutional layers and is primarily used for
image processing. Additionally, CNN is also considered as a regu-
larized edition of MLP (Figure 8). CNN are completely connected
networks in which each neuron in the first layer is linked to
the neuron in the next layer. A network like CNN can over-
come the overfitting problem by employing completely integrated
algorithms [89]. Hamza et al. [90] used CNN to evaluate the
10 | Noor et al.
Figure 8. Architecture of DL. In DL, each input layers takes an input and pass to the hidden layer. The hidden layer does the activation and passes
to next hidden layer until all hidden layers are reached. Finally, an output layer is reached that gives the final outcome of the algorithm [figure is
adopted/modified from Dara et Al. [72] © (2021) Springer].
molecular bioactivities of small molecules. Their study proposed
that CNN yielded impressive accuracy (90.21%). Therefore, CNN
is an efficient activity prediction approach for unknown targets.
In network pharmacology, the CNN model can be used to predict
the bioactivity of small molecules as well as to predict the binding
affinity between bioactive compounds and target proteins, which
not only improves the scoring function but also lend a helping in
upgrading the predictive capabilities.
RNN is a special type of ANN in which the output of the
preceding step is used as input to the next layer [91]. Using this, a
directed graph and a timed sequence can be generated in the net-
work. Similarly, the RNN network employs local storage to execute
groupings in input parameters. RNN was used in virtual screen-
ing to generate novel molecular libraries, which helped in the
discovery of anticancer drugs using molecular fingerprints [92]. In
network pharmacology, RNN can be used in virtual screening to
generate novel molecular libraries, which helped in the discovery
of multi-target drugs against diseases. When compared to other
traditional approaches, DL has a myriad of benefits, including the
capacity to learn complicated patterns independently. Thus, DL
has opened new avenues for the discovery of new therapeutic
options for a variety of diseases and disorders. In conclusion, sig-
nificant breakthroughs have been noticed in this domain, and new
applications and approaches are produced every day, making this
technique a dependable instrument in the armory accessible for
the discovery of new drug candidates. However, only few studies
reported the application of DL models in network pharmacology.
Therefore, further studies on the implementation of DL models
in network pharamcolgy will pave the way for multi-target drug
discovery in near future.
Challenges in training ML or DL models and their
potential solutions
Despite the convincing applications of ML and DL in drug–target
interaction identification, they do have short-comings for network
pharmacology. For example, ML model training significantly
depends on vast amounts of data [1, 93]. Model training using
traditional ML is also sensitive to distribution of data and
ratio between labels and unlabeled data instances. In network
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pharmacology, realistically, it is nearly impossible to collect a
significant proportion of labeled data. Similarly, choosing negative
data is also challenging due to the possibility of drug interaction
with more than one target. In a compound–protein interaction, if
a compound is interacting with a target protein, we considered the
interaction as positive. The remaining unknown interactions are
considered to be unlabeled interactions. Most of the previously
developed methods categorize known drug–target interactions
as positives and a subset of unknown interactions as negatives
while designing a predictive model [94]. However, unknown
interactions are not truly negative interactions, as they include
potential interactions that have not yet been validated as positive
interactions. To address this problem, Xia et al. [95] developed an
LapRLS that regards known interactions as positive and unknown
interactions as unlabeled data. Chen et al. [96] developed an
algorithm using a network-based random walk with restart
approach (RWRH). Unfortunately, these approaches are limited in
predicting the interactions of novel compounds or proteins that
do not have any known target or drug information (e.g. newly syn-
thesized compounds or mutated protein sequences). Additionally,
collecting a large amount of data is time consuming and hard to
collect.
To deal with such data limitations, semi-supervised learning
(SSL) can be seen as an alternative to traditional ML. SSL uses
extensive unlabeled data thus does not require large labeled data,
saving both time and cost. In SSL, source and target data come
from the same distribution. Chu et al. proposed an SSL-based
classifier to predict the drug–drug interactions [97]. The authors
claimed that their proposed framework showed improved perfor-
mance, by up to 10.3% over the existing state-of-the-art methods
to predict drug–drug interaction prediction. Additionally, several
studies have used SSL to answer different biological questions [95,
98, 99]. Another type of naturally similar learning to SSL is active
learning where the learning algorithm can query a user interac-
tively to label data with the desired outputs [100]. Active learn-
ing facilitates faster algorithm training by proactively identifying
high-value data points in unlabeled datasets [101]. Consistent
with SSL, active learning does not require many labeled instances
and also focuses on existing unlabeled data. In active learning,
 Machine learning for synergistic network pharmacology | 11

Table 1. Different learning technique that may be exploited to meet the challenges of network pharmacology

Network-pharmacology challenges Limitations of ML and DL methods Potential solutions

Small sample size ML and DL methods require a large amount of TL can be one possible solution to deal with data
data limitations. It uses previously trained model for related

Large amount of unlabeled data
instances
Large heterogeneous network with
non-liner associations
Knowledge-based conditions
Computing resources
Both ML and DL are sensitive to ratio between
labeled and unlabeled data instances
ML methods rely on hand-crafted features
ML and DL are data-driven
DL may require large computing resources
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tasks.
Semi-supervised or active learning make use of large
available unlabeled data instances. Hence, becoming
an effective tool for network pharmacology.
DL has the ability to simultaneously extract most
predictive features from complex biological networks
and learn from them. However, DL may have limited
interpretability.
Active learning involving the selective labeling could be
an option to use existing knowledge in labeling of data
instances.
TL can be used to mitigate the requirement of
computing resources.

the examples to be labeled are chosen carefully from large unla-
beled data. This is contracting to passive learning where targeted
examples to be labeled are chosen randomly from unlabeled data
[102, 103]. One major limitation of SSL and active learning is their
dependence on a large number of negative instances, which are
hard to define in network pharmacology.
DL methods, as mentioned above, have also gained huge
popularity due to their ability to extract features from raw
data instead of relying on hand crafted features (required in
traditional ML). The ability of DL methods to extract features and
analyze data simultaneously is proving them as real problem-
solving methods [104, 105]. However, along with large data
requirements, DL methods have another challenge of a large
number of parameters associated with them. Training a DL model
and determining an optimal value for it from a large number
of parameters is time taking and demands huge computing
resources that might be missing in young and emerging labs.
In addition, interpretation from deeply trained models is difficult
[106].
Transfer learning (TL) addresses the shortcomings of required
time and necessary data amount and distribution for model
training [107]. TL is an ML method where knowledge obtained
from a model used in one task is reused as the foundation for
another task [108]. TL aims for transferring knowledge across
the domains and based on similar datasets and infer relatedness
between these datasets using ML algorithms. TL also differs from
SSL in terms of required distribution of data. TL is independent
of distribution in input data, which is a core requirement in
SSL [109]. One of the most famous TL transformers for lan-
guage representation models is Bidirectional Encoder Represen-
tations from Transformers (BERT) [110]. Language representation
models are hard to train and have been using TL frequently
to capture [111] text semantics. BERT architecture is a multi-
layer bidirectional transformer and has been trained on plain
text. BioBERT [112] is biomedical version of BERT and its train-
ing data are restricted to the biomedical domain. Both BERT
and BioBERT have been extensively used for the prediction of
drug–drug interaction or drug–target interaction [113–115]. TL,
when combined with deep or traditional ML, can be an effec-
tive tool to address the current challenges in network pharma-
cology. Table 1 provides a quick overview of different learning
techniques.
TRANSFORMING NETWORK
PHARMACOLOGY THROUGH ARTIFICIAL
INTELLIGENCE AND ML TECHNIQUES
The conclusive applications of ML and DL methods in every
field of life have enhanced their popularity. To meet this surge,
several libraries and frameworks have been developed. The pur-
pose of developed libraries and frameworks was to ease the
implementations of learning methods, thus allowing researchers
from different disciplines to apply sophisticated mathematical
methods without their deeper understanding [116, 117]. Python
and R programming languages have been frequently used to apply
ML or DL methods on a given task. For example, scikit-learn
[118] and Caret [119], developed in python and R, respectively,
are two commonly used libraries to apply traditional ML. Pytorch,
keras, tensorf low [120] are more specialized libraries for DL in
python and have been widely used for training of different DL
classifiers. Pytorch is written in python programming language
and enables its users to apply CNN, RNN and LSTM like familiar
deep architectures [121, 122]. Another popular framework for DL is
tensorf low that is operable on heterogeneous operating systems.
Tensorf low is written in Python and C++ and provides the facility
of applying CNN, RNN, LSTM and other DL methods [123]. Keras is
another python-based library with extensive documentation and
active community. It can also be utilized to apply different DL
architectures [124].
Another integral component of analyzing big data is the scala-
bility of the proposed architectures. Cloud computing has been
extensively used for many life science challenges. Cloud com-
puting describes both a platform and a type of application. A
cloud computing platform dynamically provisions, configures,
reconfigures and deprovisions servers as needed. On the other
hand, cloud applications are extended to be accessible through
the Internet. These cloud applications use large data centers and
powerful servers that host web applications and web services
[125]. Unfortunately, the usage of distributed or parallel comput-
ing through cloud computing is lagging behind in case of DL,
more specifically in biomedical sciences. Despite the availability
of cloud-based frameworks such as Apache Spark and Elastic
search, applications of cloud computing are limited in biomedical
data sciences. Apache Spark [126] is one of the most used uni-
fied analytics engines for processing large health or life science
datasets. The ease of writing code in multiple languages and
12 | Noor et al.
easily understandable structure allowed the implementation of
DL architectures in the cloud. Elastic search is another framework
that works for almost all types of data and has been used by
leading bioinformatics research groups. However, for the majority
of research groups, it is quite challenging to establish cloud-based
infrastructure due to its maintenance, lack of skillful people and
future research thematic lines. Most of the data producing groups
are not fully equipped with experts in data analytics. Nvidia Clara
framework [127] provides a pre-trained model, thus eliminating
the need of highly skilled experts for the discovery of drugs.
One major limitation of cloud-based framework is data privacy
and concerns linked to data security [128, 129]. To compensate
for such data security concerns, federated computing is rapidly
emerging [130, 131]. In federated learning, researchers or orga-
nizations collaborate on their ML or DL projects without sharing
real and sensitive data, for example, patients’ data and treatment
response in case of drug therapy. Federated computing is still
an emerging field and in future it will have a significant role
in network pharmacology. Table 2 provides an overview of tools
available for the discovery of potential drug candidates based
on ML and DL algorithms. The first two columns provide a brief
description and method used behind the development of that
particular tool. The third column provides information related to
accuracy percentage of each tool, which indicates that how often
a model trained is correct. The exclusive features and limitations
of each tool are enlisted in the last two columns. Overall, the main
advantage of providing this table is that it provides a clear picture
of available ML and DL tools that can be used at different stages
of network pharmacology pipeline. This will assist the researchers
to integrate both ML and DL in network pharmacology for multi-
target drug discovery, which ultimately shortens time-consuming
procedures and manual operations.
With recent advancements in network pharmacology research
techniques, it is hoped that further network-based analytical
approaches would be integrated into different medical areas
to speed up the process of multi-target drug discovery. In a
nutshell, the field of drug development is shifting toward network
pharmacology [14], but this approach faces challenges with
computational cost, time and reliability, although ML or DL offers
promising solutions to overcome these barriers and advance
the role of computational techniques in network pharmacology
(Figure 9). Thus, the combination of ML with network pharma-
cology is considered an important topic of biomedical sciences.
Regarding this, some application of ML that can be applied on
network pharmacology research is discussed below in order to
produce enthralling and promising therapeutic agents against
complex diseases.
Predicting bioactivity and physicochemical
properties of small molecules
Bioacivitiy assessment is a laborious and time-sapping process
in the drug discovery pipeline. Several web applications have
recently been introduced to evaluate the bioactivity of small
molecules [132]. But these in silico-based analysis required bench-
mark datasets for validation. To tackle this issue, ML approaches
are currently used by researchers to identify the bioactivity of
compounds which are then used to treat specific disease tar-
gets. Many studies provide solid evidence of ML applications in
bioactivity prediction. For example, Zhi et al. [133] used net-
work pharmacology and molecular docking, which revealed dihy-
droorotate dehydrogenase (DHODH) as a therapeutic target for
Small cell lung cancer. Later, they build predicted model using
Graph Neural Networks (GNN), SVM and RF. GNN are class of
DL method which directly operates on the graph structure. GNNs
captured the internal information directly from the graph struc-
ture, which means the SMILES of the molecules are transformed
to a graph representation of molecules. The performance of multi-
GNNs was reliable and was better than that of the ML and
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single GNN. The strategy of combining a global approach and a
local approach resulted into improved model performance. The
findings of their study proposed that ZINC95618747, ZINC8577218
and ZINC4261765 are effective inhibitors for DHODH.
It is well known that each compound has some chemi-
cals and physical properties including permeability, solubility,
ionization and partition coefficient which interfere with the
pharmacodynamics and pharmacokinetics of compounds [134,
135]. Therefore, when formulating a novel drug molecule, the
physicochemical properties of compounds must be taken into
account. The physicochemical properties of chemical compounds
has now been predicted using a variety of ML-based approaches
[136]. Lusci et al. [137] introduced a framework based on a neural
network to anticipate the molecular characteristics. Their work
uses undirected cyclic graphs to classify molecules, whereas
the earlier models for estimating physicochemical properties
used directed acyclic graphs. Their proposed model has ability
to automatically extract internal representations from the
molecular graphs that are well suited for the specific tasks. This
aspect is an important advantage for a problem like aqueous
solubility prediction, where the optimal feature set is unknown
and their number may differ from one data set to the other. It
also saves time and avoids other costs and limitations associated
with the use of human expertise to select features. Additionally,
various ML-based applications are widely used nowadays such
as SPARC (http://sparc.chem.uga.edu/sparc/) [138], ChemSpider
(http://www.chemspider.com/) [139], E-DRAGON (http://www.
vcclab.org/lab/edragon/), OSIRIS property explorer (https://www.
organic-chemistry.org/prog/peo/) [140], PCLIENT (http://www.
vcclab.org/lab/pclient/) [141], E-BABEL (http://www.vcclab.org/
lab/babel/) [141] and ASNN (http://www.vcclab.org/lab/asnn/)
[142]. The aforementioned data support the significance of DL
and ML algorithms in the prediction of physiochemical properties
and bioactivity of drug molecules. From a research standpoint,
the validation and preciseness of these algorithms remain a
negative aspect. As a result, substantial research needs to be
conducted to maximize the accuracy and reliability of AI-based
approaches via tailored and substantial data input. Thus, in
network pharmacology, ML-based algorithms might help in the
screening of bioactive compounds on the basis of their bioactivity
and provide theoretic evidence for the synergistic effects of small
molecules for treatments of ailments.
Target identification
Identification of potential targets is considered as the backbone
of network pharmacology research. Without foreknowledge of
the complete compound and disease target information, it is
impossible to design effective and budget-friendly approaches for
the treatments [143]. A huge amount of data can be obtained from
databases, literature and lab experiments. However, extracting
meaningful information from the bulk of data is a challenging
task. To tackle this issue, ML approaches are being used for
the identification of both compound and disease-related targets.
Laura et al. [144] introduced a multi-network-based strategy to
integrate multi-network-based strategy to combine multiple lay-
ers of genomic information, particularly gene co-expression, PPI,
miRNA co-targeting and transcription factor co-targeting for iden-
tification of cancer-related targets. The proposed multi-network
Table 2. The list of ML-based tools available for the discovery of potential drug candidates

Tool and software Description Method Exclusive feature Limitation Ref.

ML-based methods
QSAR-Co-X Fully accessible QSAR modeling tools for
multiple targets.
Cloud 3D-QSAR An online application for developing QSAR
models for drug discovery.
OntoQSAR An Ontology for QSAR Studies to Evaluate
Biological and Chemical Data
DrugNet Using heterogeneous data to prioritize
diseases and drugs in a network
DrPOCS Drug Repositioning on the basis of Convex
Sets Projection
Chembench A hub of cheminformatics
mCSM-lig Structure-guided computational methodology
for measuring the significant effect of single
missense mutations on the affinities of active
compounds for proteins
CSM-lig Online portal for predicting the binding
affinity of a protein–compound complex.
mCSM-AB A user-friendly web server that can estimate
antibody–antigen affinity with high accuracy
dendPoint Web-server for predicting and analyzing for
dendrimer pharmacokinetics
Vienna LiverTox Model used for predicting interaction between
compounds and transporter of regulatory
agencies
RepCOOL Repositioning of drugs computationally by
merging diverse biological networks
WGMFDDA A novel weighted-based Graph regularized
matrix factorization to predict association
between compound and diseases
ML and classification Build a specific model equation from a variety ML requires unbiased good quality data for [195]
model of biological and chemical data. processing, it requires sufficient time for
ML Merging the sciences of molecular processing the input data with a considerable [196]
interactions, alignments and structure amount of accuracy. Other major challenges
formation are high error-openness and interpretation of
ML and Retrieve the biological characteristics and results. In ML, we have to run our data in all [197]
mathematical model chemical descriptors of active ingredients. algorithms to select the most ideal algorithm
ML Drug repositioning efforts can be greatly and the selection is based on the result [198]
enhanced by integrating disease, drug and accuracy. This is a time taking process which
target information together. may affect the further procedure. ML
Machine learning With matrix completion, DrPOCS forecasts approaches are not so convenient for [199]
potential connections between drugs and high-level, symbolic reasoning, or planning
disorders. which creates difficulty to understand all
Machine learning Open platform that allows investigators to aspects of natural language [200]
access and exploit existing biological and
chemical data
Machine learning Giving valuable hints for assessment of [201]
models, Platinum genotyping and directing drug development. It
database is efficient in detecting a variety of
chemotherapeutic, antiviral and antibacterial
resistant variants
Machine learning, Estimate binding affinities evaluate the [202]
graph-based interaction between molecules in docked
chemical signatures complexes
based on PDBbind
databases
Machine learning Used graph-based signatures to predict [203]
antibody–antigen affinity
Machine learning and Machine learning-based model capable of [204]
principal component accurately predicting pharmacokinetic
analysis parameters
Machine learning Analyze the pharmacokinetic properties [205]
classification model
Random Forest The effectiveness of the suggested technique [206]
classifier in identifying actual drug–disease correlations
K -nearest neighbor To uncover unidentified active [207]
compound–disease relationships, the graph
regularised matrix factorization framework is
used. 10-fold cross-validation is carried out on
the Fdataset to assess the performance of
proposed WGMFDDA method.
Machine learning for synergistic network pharmacology
|

(Continued)
13

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 14
|

Table 2. Continued
Tool and software Description Method Exclusive feature Limitation Ref.
Noor et al.

ProTox-II Predict toxicity of bioactive compounds
adsorption, distribution, metabolism and
excretion
ADMETlab Database for predicting adsorption,
distribution, metabolism, excretion and
toxicity (ADMET) of active compounds
Deep-learning-based
ChemGrapher Identification of chemical compounds using
optical graphs
HeteroDualNet A unique convolutional network with
heterogeneous layers and dual branches
SAEROF To understand new features effectively
representing drug–disease associations
DeepConv-DTI Used to train, validate and test deep learning
model for prediction of compound–target
interaction
DeepH-DTA Prediction of compound–target interaction
DeepH-DTA Prediction of compound–target interaction
IDDkin Identification of kinase inhibitors
Quantum-Based
COSMOfrag a brand-new method based on quantum chemistry for
high-throughput adsorption, distribution, metabolism and excretion
property prediction Quantum Chemistry
Molecular similarity, Predicts cytotoxicity, carcinogenicity, [208]
fragment hepatotoxicity, acute toxicity, mutagenicity,
propensities and immunotoxicity
machine learning
ML Systematic ADMET evaluation based on a [209]
large and structurally diverse data sets.
Deep learning Generates all the necessary information to DL lacks common sense. This makes the [210]
link each resultant graph component to its systems fragile and when errors are made, the
corresponding source image. errors can be very large. Once trained, DL
models become inf lexible and cannot handle
multitasking. They can deliver efficient and
accurate solutions but only to one specific
problem. Even solving a similar problem
would require retraining the system.
Convolutional Neural Used heterogeneous layers to predict the [211]
Network compound/ drug–disease association
Deep Neural Network Simple but effective approach to analyze the [212]
association between compound and diseases
Deep learning A prediction model that efficiently improves [213]
the characteristics of a raw protein sequence
for the purpose of recognizing local residue
patterns of target proteins produces more
improved outcome than earlier methods
Deep learning Geometrically exploits the topological [214]
structure and corresponding molecular
fingerprints of plant related compounds
Deep learning Geometrically exploits the topological [214]
structure and corresponding molecular
fingerprints of plant related compounds
Deep diffusion model In silico method integrating data from [215]
different resources to predict the kinase
inhibitors
Used quantum chemistry for predicting the [216]
adsorption, distribution, metabolism and
excretion properties of plant related
compounds

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 Machine learning for synergistic network pharmacology | 15

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Figure 9. Advancing network pharmacology research via ML. A superpower to fight against the deadliest diseases. DL CNN, DNN, RNN and MLP holds
promise for drug development as it allows the prediction of molecular structure and function, and the automated development of novel chemical entities
with specific features. Following that, SVM and RF has spotlighted recently as they significantly applied to handle big data challenges in network
pharmacology research. Thus, ML approaches facilitate the development of drugs with multi-target effects and exploring the poly-pharmacology of
different currently used drugs.

strategy is perfectly suited to identify these potential miRNA
drivers since one of the layers is exactly the miRNA co-targeting
network and, in this case, the role of the other layers is to filter
among all the miRNAs only those whose targets also interact in
one or more of the other layers and in particular in the cancer
co-expression one. The authors used consensus clustering algo-
rithm of ML on the predicted network which uncovered CD46,
BTG2, ATF3, HDGF and F11R as driver cancer genes. In short,
such kind of multi-network-based analysis provide encouraging
evidence that multilayer networks contain new information on
the structure and dynamics of complex systems, which would not
be possible to get from the individual components. Beyond this,
group of researchers proposed DEcRyPT method for multi-target
drug discovery [145, 146]. DecRyPT method used the RF algorithm
that contributed to a preferential exploration of disease-related
targets. Consequently, ML models offered a quantitative frame-
work to identify the promising targets for discovery of novel drug
candidates. In the context of network pharmacology, researchers
rely on literature and databases for target identification. However,
identification of compound and disease-related targets using ML
technqiues can be helpful for researchers to get a better under-
standing of targets.
Identification of molecular pathways
Pathways analysis is a crucial step in network pharmacology as it
is intended to give some special meaning to high-throughput bio-
logical data [147]. Despite their extensive usage, the context and
fundamentals of pathway analysis may not be fully understood,
which ultimately led to false results [148]. To overcome these
problems, ML are extensively used for pathway analysis. Inte-
gration of ML techniques with pathway analysis provides a new
insight for predicting the molecular targets of multiple diseases
and disorders. STRING [149], STITCH [150] and DisGeNET [151]
are widely used in network pharmacology for the identification of
molecular pathways in which dysregulation leads to disease con-
ditions. In short, the birth of ML in pharmaceutical research has
made it possible to find molecular targets or pathways of human
16 | Noor et al.
diseases using genomic data. A number of techniques for discov-
ering (or designing) novel pathways have been proposed, including
search-based methods which identify plausible paths between
given input and output metabolites. Other approaches include
searching for frequently-occurring patterns of molecular func-
tions in biological networks or kernel-based methods for learning
associations between enzymes catalyzing successive functions
in metabolic pathways [152]. Dongardive et al. [153] used ML
classifier techniques for pathway identification. The authors used
five different ML classifier to detect molecular pathways involved
in viral infections and cancer. The authors applied five different
ML classifiers to determine the accuracy of the classification. The
overall results showed that ML classifiers could be able to give a
range of accuracy of 71–72%. Overall, RF gave the highest accuracy,
which indicates that RF technique and the proposed method
might be efficient in classifying the cancer and viral metabolic
pathways. Thus, RF methods can be used in network pharmacol-
ogy for identification of metabolic pathways. Similarly, Hao et al.
[154] introduced PASNet, the first DNN that presents a hierarchi-
cal representations of genes, pathways and their nonlinear effects.
PASNet models a multi-layered, hierarchical biological system of
genes and pathways to predict clinical outcomes by leveraging DL.
The sparse solution of PASNet provides the capability of model
interpretability that most conventional fully-connected neural
networks lack. In the context of network pharmacology, the use
of PASNet can provide a better understanding of metabolic path-
ways. Although ML-based approaches play key roles in construct-
ing and understanding metabolic pathways and their subparts,
the prediction and construction of synthetic metabolic pathways
is a significant challenge in network phramacology research.
Prediction of PPIs
PPIs are the center of network pharmacology. PPI analysis is essen-
tial for designing efficient drugs as it plays a key role in the cellular
systems of all living organisms [155]. Large PPI data produced by
high-throughput techniques gave boost to a new drug discovery
era that ultimately became the basis of new biological discoveries.
Managing, evaluating and modeling PPI data is a primary chal-
lenge in network pharmacology [156]. These issues are currently
addressed by ML approaches which uses various data sets, input
attributes and architectures to predict PPIs. Furthermore, recent
studies claim that DL is the most effective approach for predicting
PPIs [157].
Hashemifar et al. [136] introduced DPPI (https://github.com/
hashemifar/DPPI/), a novel DL framework for predicting PPI. DPPI
used only sequence information and then predict interactions
between proteins. DPPI uses CNN model and effectively mea-
sures interactions by combining pre-existing experimental PPI
data and evolutionary information of protein pair under predic-
tion. Du et al. [158] proposed a cutting-edge method known as
DeepPPI (http://ailab.ahu.edu.cn:8087/DeepPPI/index.html) that
uses DNN to effectively learn the representations of proteins from
common protein descriptors. The experimental results demon-
strate that DeepPPI outperforms on the test data set, specificity
of 94.49%, recall of 90.56%, precision of 94.38% and accuracy
of 92.50%, respectively. One factor that contributes to the good
performance of DeepPPI that it can learn useful features of pro-
teins pairs by a layer-wise abstraction. Another factor is the
DeepPPI can learn an internal distributed feature representation
automatically from the data. These characteristics are proved
to be an effective approach to learning representations of pro-
teins. Further, PPI_SVM [159] (http://code.google.com/p/cmater-
bioinfo/), an efficient knowledge-based prediction method, was
evolved in 2011 to prefigure the PPIs based on frequency counts,
domain-domain interactions and ML. Beyond this, Chen et al.
[160] developed an ensemble learning approach for PPI predic-
tion that integrated multiple learning algorithms and different
protein-pair representations. The authors adopted a stacked gen-
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eralization scheme and develop a classifier called PPI-MetaGO,
which improves PPI prediction by deducing the biases of the
base generalizers and exploiting the synergy among various ML
algorithms. Many examples of ML role in PPI prediction has been
discussed, and the PPIs research is still in progress. However,
designing PPI modulators continues to be a tricky problem, and
is typically endorsed by a comprehensive understanding of the
system at the molecular and structural levels. In terms of network
pharmacology, PPIs networks are being used more frequently
as universal platforms for the analysis and integration of data.
Therefore, these models can be implemented in network phar-
macology, which provides a helping hand in multi-target discov-
ery. Altogether, gaining a better understanding of PPIs using ML
approaches will allow researchers to unveil the therapeutically
relevant aspects of PPIs to treat human diseases.
Network analysis
Recent studies on biological networks, including metabolic, gene
regulatory and PPI networks, have contributed to understanding
the origins of cellular behaviors and evolutionary design princi-
ples, as well as specific cell biological processes or diseases [161].
In terms of network pharmacology, network analysis provides
novel insights in understanding the interactions among biologi-
cal entities, such as bioactive compounds, targets, diseases and
pathways [162]. In pharmacological studies, multiple active com-
pounds can target one gene, and one compound can target mul-
tiple genes, which necessitates the construction of compound–
target and compound–target–pathway networks [163]. However,
constructing such networks is challenging and prone to high
false-positive rates. Therefore, extracting key sub-networks and
identifying overlapping networks is crucial to identify the key
components in the network.
ML-based algorithms are effective method to process the bio-
logical network data, so as to implement classification, cluster-
ing and prediction tasks in a biological network. Therefore, ML
can effectively predict the multitarget mechanisms underlying
the effects of active compound against diseases. Recently, Zeng
et al. [164] introduced an deepDTnet for target identification from
heterogenous networks. DeepDTnet computationally identifies
thousands of novel drug–target interactions with high accuracy
by using DNNs. DeepDTnet learn low-dimensional vectors rep-
resentations for both drugs and targets by a unique integra-
tion of large-scale chemical, genomic and phenotypic profiles.
Owing to the lack of experimentally reported negative samples
(non-interactions between drugs and targets) from the publicly
available databases, deepDTnet employed the Positive-Unlabeled
(PU)-matrix completion algorithm to low-rank matrix completion,
which is able to infer whether two drugs share a target without
negative samples as input. Similary, Zheng et al. [165] developed
THN_KRLS, an ML-based prediction method for tripartite hetero-
geneous network. THN_KRLS combining multiple kernels into a
tripartite heterogeneous drug–target–disease interaction spaces
in order to integrate multiple sources of biological information
simultaneously. This novel network algorithm extends the tradi-
tional drug–target interaction bipartite graph to the third disease
layer. Following that, ML can be implemented in network phar-
macology not only for efficient handling of high throughput, het-
erogeneous and complex molecular data, but also for mining of

feature or relationship in the ‘compound-target’ and ‘compound-
target-pathway’ network. In the context of network pharmacol-
ogy, these kind of ML algorithms will help in predicting affinity
values within ‘compound-target’ network which will explore more
core compounds and core target. To sum up, the ML model lend a
helping hand in the identification of multi-target compounds for
given target proteins based on their involvement in pathways in
which dysregulation leads to disease conditions.
Hub gene analysis
Topological analysis of PPI network is used to identify hub genes
related to disease. Hub genes are those genes having high degree
of connectivity in gene network, suggesting functional impor-
tance in the diseases [166]. High connectivity means that the
connectivity ranked at top 10%. As for example, if the size of
module is 10,000, then the top 1000 genes are considered as
the hub genes [167]. Therefore, accurate identification of hub
genes is crucial to design multi-target drugs. Nowadays, ML with
its powerful models are used to predict hub genes from gene
networks. Recently, Liu et al. [168] identified nine-hub-gene sig-
nature of metabolic syndrome using integrated bioinformatics
analysis and RF method. This nine-hub-gene signature showed
better calibration and classification performance (AUC = 0.861 in
external validation set, AUC = 0.968 in training set and AUC = 0.883
in internal validation set). Similarly, Li et al. [169] applied RF meth-
ods to identify the stromal-related features of the two modules
at a single-gene level. Their study proposed 71 hub genes that
can be used as a biomarker for esophageal adenocarcinoma and
squamous cell carcinoma. Spotting the benefits provided by ML
approaches for hub gene analysis, we strongly believe that these
ML approaches can be used in network pharmacology for the
identification of hub genes which not only provide promising
therapeutic target of disease but also accelerate the process of
multi-target drug discovery.
Prediction of the mode of action and toxicity of
compounds
Compound toxicity is the degree to which active ingredients or
a particular chemical substance can damage an organism. With
the advent of ML techniques, the resources, time and cost of
designing candidate drugs is decreased to an unprecedented level.
ML offers a helping hand by developing multiple tool/software to
determine the toxicity of compounds including Tox21 (https://
ntp.niehs.nih.gov/whatwestudy/tox21/index.html) [170], Toxtree
(http://toxtree.sourceforge.net/) [171], admetSAR (http://lmmd.
ecust.edu.cn/admetsar2/) [172], TargeTox (https://github.com/
artem-lysenko/TargeTox) [173], SEA (http://sea.bkslab.org/) [174],
eToxPred (https://www.brylinski.org/etoxpred-0) [175], pkCSM
(http://biosig.unimelb.edu.au/pkcsm/) [176] and LimTox (http://
limtox.bioinfo.cnio.es/) [177]. Mayr et al. [178] developed DeepTox
pipeline for toxicity prediction. DeepTox first normalizes the
representation of chemical compounds. Next, it computed
chemical descriptors that are used as input in ML techniques.
After that, it build models and then trained the model. Later, the
performance of the trained model are then evaluated. Finally, the
well-trained model is used to predict the toxicity of the active
compound.
Understanding a biologically active compound’s mechanism of
action entails not only identifying the target but also investigating
the biological chemistry that occurs before or after target binding.
Gururaj et al. [179] introduced a web application through which a
user can input a custom testing features data-set containing gene
expression and cell viability levels. The output produced is the
Machine learning for synergistic network pharmacology | 17
top classes of drugs, along with their scatter plot. This can help
scientists to predict the action mechanisms and can help them
in the discovery of new drugs. Gao et al. [180] developed Genetic
profile–activity relationship (GPAR) to help modeling and predict-
ing action mechanisms easily via DL. The users can use GPAR
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to customize their training sets to train self-defined predictions
models, to evaluate the model performances and to make further
predictions automatically. Cross-validation tests show GPAR out-
performs gene set enrichment analysis in predicting mechanism
of actions. Similarly, Liu et al. [181] and Fronsdal et al. [182] used
DL models and predict action mechanisms of compounds. Their
studies highlighted the importance of DL models for understand-
ing the action mechanisms of novel drugs. Implementation of
DL models in network pharmacology for predicting toxicity and
actions mechanism might reveal efficacy and synergistic effect of
compounds.
Integrating ML systems for improving docking
prediction reliability
In network pharmacology, the pressing need of the hour is to
grasp poly-pharmacological effects of compounds and to develop
computational algorithms to accurately predict the effect of com-
pounds across the molecular network. To achieve this, high-
throughput molecular docking simulation systems must be con-
structed to calculate the combined effects of compounds through
molecular networks. ML is often presented as a new industrial
revolution. The sampling, scoring and computing time are three
main challenges of molecular docking. Nowadays, researchers
are using ML algorithms to overcome these challenges. Recently,
Google’s sister company, DeepMind, in London, developed an ML-
based tool named as AlphaFold for predicting the structure of
target protein [183]. Following that, another tool RoseTTAFold has
been developed that uses DL to quickly and accurately predict
the protein structures based on limited information [184]. After
successfully predicting the 3D structure of target protein, docking
analysis is performed to predict the binding affinity between
compound and target proteins. In ML, a model is trained using
training data (active/inactive compounds). The trained model is
then tested for accuracy, and if it passes muster, it is applied to
fresh datasets to figure out compounds for desired activity against
a target [185]. The finalist compounds are then undergo ADMET
analysis, including several bioassays prior to entering in clinical
research.
In network pharmacology, target docking is used for validation
of interaction that exists between target and compound. Regard-
ing this, various ML algorithm including SVR-Score, NNScore, ID-
score and CScore has now been developed for target docking
[186]. In the same vein, many other algorithms CNNs, RFs, shallow
neural networks and SVM are used for the prediction of binding
affinity between protein-compound. Kwon et al. [187] introduced
AK-score that predicts protein-ligand binding affinity based on
the ensemble model of three-dimensional neural network. Sim-
ilarly, Amangeldiuly et al. used SVM and RF to predict binding
affinity between protein and ligands. Qamar et al. [188] reported
that target-specific ML scoring function has better performance
compared to the classical generic scoring function in ranking
biologicaly active molecules against the target enzymes during
drug discovery. Hsin et al. [189] combined ML approaches with
docking simulation to improve the reliability of docking analysis
in network pharmacology. In summary, the implementation of ML
techniques makes its simpler with high accuracy and precision.
The combination of ML techniques with network pharmacology
shows a remarkable advantage in highlighting the systematic
18 | Noor et al.
biological network. With ML, network pharmacology has trans-
formed into a potent tool for interpreting the biologically active
compounds and possible targets of herbal remedies.
Clinical trials
ML have the potential to add much value to a clinical trial by
facilitating decision-making, reducing the time to complete the
trial, and the overall drug development process. ML approaches
are available to analyze large and heterogeneous data, identifying
intricate and occult patterns and predicting complex outcomes.
As a result, ML has value to add across the spectrum of clin-
ical trials, from preclinical drug discovery to pre-trial planning
through study execution to data management and analysis. For
example, a treatment that is effective against early manifestation
might not be effective against late manifestation. In such cases,
Heterogeneous Treatment Effect (HTE) analysis can be extremely
useful in finding subgroups consisting of patients who have sim-
ilar covariates and display similar treatment responses. In the
context of a clinical trial, HTE analysis can increase the likelihood
of identifying subgroups of the population for whom a particular
treatment is effective, even when it is found to be ineffective
for the population as a whole. Using ML, Rouillard et al. [190]
assessed omics data for a set of 332 targets that succeeded or
failed phase III clinical trials by multivariate feature selection.
They found gene expression data were particularly predictive of
successful targets, characterized by low mean RNA expression
and high variance across tissues. This study confirmed previous
findings that ideal targets exhibit disease-specific expression in
affected tissues. Bisaso et al. [191] observed a steady growth
in the application of ML in HIV clinical research. Despite the
dominance of statistical analysis as an application paradigm, ML
usage is steadily diversifying to include practical clinical tools
to assist in clinical decision making. The use of high-dimension
sources of data such as genomic data has overtaken other data
sources and this has been attended by an increase in use of
high performance non-parametric ML methods with a focus on
combating resistance to antiretroviral therapy. To the extent that
ML-enabled clinical research can improve the efficiency and qual-
ity of biomedical evidence, ML innovation has given new essen-
tiality to network pharmacology. With more clinical data and
with availablity of more reboust ML methods, it is expected that
ML-based approaches will have significant impact onnetwork
pharmacology and will become the standard computer-supported
medication plan strategy.
To sum up, the ML models may be different each time they are
trained. In turn, the models may make different predictions, and
when evaluated, may have a different level of error or accuracy.
The amount of difference in the results will be related to how
different the training data is for each model, and the variance
of the specific model and model configuration chosen. A more
sensitive algorithm has a larger variance, which will result in
more difference in the model and, in turn, the predictions made
and evaluation of the model. Conversely, a less sensitive algo-
rithm has a smaller variance and will result in less difference
in the resulting model with different training data and, in turn,
less difference in the resulting predictions and model evalua-
tion. Thus, the ML model is making different predictions each
time it is trained, even when it is trained on the same data set
each time. Table 3 enlists the ML methods used at each step of
network pharmacology, their general workf low with their short
description. The methods mentioned here capture many of the
key areas of how ML and DL can inf luence the multi-target drug
discovery. Nonetheless, this is still an active area of research with
novel applications of DL and ML algorithms continuously being
developed.
ONGOING CHALLENGES IN ADOPTING ML:
LEADS ON WAYS TO OVERCOME THE
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LIMITATION OF NETWORK
PHARMACOLOGY
Drug research benefits from network pharmacology will aid in
the resurgence of traditional knowledge. Despite that, there are
several drawbacks of adopting ML in network pharmacology that
would hopefully get resolved in the future. First, the availability
of a large amount of data is critical to the success of ML because
these data are used for the subsequent training provided to the
system. Secondly, a corporation may incur additional fees when
accessing data from several database. Thirdly, data must also be
trustworthy and of good quality to provide accurate result predic-
tion. Many other barriers to full-f ledged ML adoption in network
pharmacology included availability of qualified professionalist
to operate AI-based platforms, insufficient resources for smaller
companies, fear of replacing workers, which could result in a loss
of jobs, uncertainty about the data generated by ML and the black
box phenomenon.
With the passage of time, specific tasks related to drug devel-
opment, production, clinical trials, supply chains and sales will
be automated; however, these all tasks fall under the bracket
of ‘narrow ML,’ in which ML must be trained by bulk of data
in order to be appropriate for a specific activity. Thus, human
involvement is crucial for effective designing and impelmenta-
tion of the ML platform in network pharmacology, although ML
is already replacing monotonous jobs, which leaves plenty of
room for incorporating human intelligence for exploring more
sophisticated insights and creativity in the field of drug devel-
opment. To date, bioinformatics is gaining popularity in every
aspect of the life sciences [192]. One of the major thrusts of
current bioinformatics approaches is the prediction and identifi-
cation of biologically active candidates and mining and storage of
related information [193]. Another interesting aspect of bioinfor-
matics is the ability to utilize high-throughput data and computa-
tional methods to predict potential synergistic drug combinations
[194]. Following that, bioinformatics in coordination with ML can
help to streamline the drug discovery process and increase the
chances of success by identifying combinations of drugs that
have the potential to produce a more potent therapeutic effect
while reducing toxicity. Further, current bioinformatics methods
help in addressing the challenges posed by large amounts of
unlabeled data in network pharmacology by leveraging compu-
tational methods to organize, process and analyze vast amounts
of data. Overall, with the development of innovative computa-
tional analysis combined with the increasing amount of relevant
biomedical information, it could be the ‘perfect storm’ for bioin-
formatics to address some of the challenges faced by network
pharmacology to discover efficacious multi-target drugs of the
future.
Untill now, only a few network pharmacology-based studies
used ML at some specific stages particularly for compound-
related target prediction and diseases-related target prediction.
However, network pharmacology is lagging behind in the race
of using ML for developing more entrailing treatment options
against deadliest diseases and disorders. Despite mentioned
limitations, the combination of ML approaches with network
pharmacology is warmly welcomed by the scientific community
because it provides a new insight to the esoteric knowledge
Table 3. Application of ML and deep learning principles in network pharmacology for multi-target drug discovery

Sr. No# Steps Methods/tools General workflow Description

1 Predicting Lusci et al. [137] • This framework employed Undirected Graph Recursive Neural Networks • The UGRNN method shown to be able to build predictive solubility
bioactivity and framework (UGRNN) which first transforms molecular structures into vectors of the same models that were comparable in accuracy to models built with molecular
physicochemical length as the molecular representation and then passes them to a fully descriptors.
properties of connected neural networks layer to build models for prediction
small molecules

Zhi et al. [133] • Graph neural networks (GNNs) used to build reliable predicted models for • The proposed pipeline identifies novel targets related to dihydroorotate
study discovering new dihydroorotate dehydrogenase protein inhibitors for small cell dehydrogenase (DHODH) and to screen drug candidates for their potential
lung cancer to inhibit multiple targets in small cell lung cancer.

2 Target Cantini et al. • This network-based workflow used an expression dataset supplied by the user, • The combination of the different layers of information allowed us to
identification [144] creates the four-layer multi-network [(i) transcription factor (TF) co-targeting extract from the multi-network indications on the regulatory pattern and
network-based network, (ii) microRNA co-targeting network, (iii) protein–protein interaction functional role of both the already known and the new candidate driver
biology analysis (PPI) network and (iv) gene co-expression network)] and provides as output the genes.
workflow multi-network community structure
• The authors applied a consensus clustering algorithm (An ML-based biology
analysis algorithm that divide the network into sub-modules with different
functions) on identified network communities to discover cancer driver genes

Drug–Target • DEcRyPT method uses regression RF as an orthogonal learning approach to • DEcRyPT can effectively advance early natural product-based drug
Relationship self-organizing maps. It harnesses a user-defined number of predictors discovery, and can be a swift alternative to chemoproteomics and work
Predictor (decision trees) that independently analyze different portions of the training as a general strategy for systems pharmacology studies.
(DEcRyPT) [146] data, before aggregation of the resulting predicted outputs.
method • When applied to celastrol, DEcRyPT method unveiled modulation of
cannabinoid receptors by celastrol, which are implicated in cancer progression

3 Identification of Pathway- • PASNet builds a network model by leveraging prior biological knowledge of • Pathway-Associated Sparse Deep Neural Network (PASNet) outperformed
molecular associated pathway databases and by taking hierarchical nonlinear relationships of other models to predict the outcome of glioblastoma multiforme (GBM)
pathways sparse Deep biological processes into account with an AUC of 0.66
Neural Network • To improve the model interpretability, PASNet introduced sparse coding to
(PASNet) [154] capture significant components of a biological mechanism in the model

Dongardive • The author collected data from metabolic networks of six different types of • Pathway-based RF classification allows us to learn more from the
et al. [153] cancer pathways and used different ML classifier to determine the accuracy of biological system rather than looking at individual genes, examine how
method the classification for selected datasets various pathways are interconnected and investigate the shared
components among different pathways

4 Prediction of DPPI [136] • DPPI divided a protein into subsequences, and used these subsequences to • DPPI efficiently model and predict PPIs from sequence and is generalizable
protein–protein perform multiple sequence alignment through PSI-BLAST to obtain a protein to many applications including the prediction of model binding affinities
interactions (PPI) profile. This is then fed to a convolutional module and a random projection
module to predict PPIs

DeepPPI [158] • DeepPPI used a Deep Neural Network architecture network for each protein to
extract high-level discriminative features from common protein descriptors
• This method comprises two different architectures: DeepPPI-Sep, which uses
two separate networks as input for each protein, and DeepPPI-Con, which
directly links two proteins in a single network
• DeepPPI capture informative features of protein pairs by a layer-wise
abstraction.
• In addition, DeepPPI can automatically learn an internal distributed
feature representation from the data.

PPI_SVM [159] • PPI_SVM uses SVM to predict interactions between two protein sequences by • PPI_SVM not only consider all possible interactions between constituent
exploiting their domain information. domains of interacting protein pairs but also determining interaction
Machine learning for synergistic network pharmacology

affinity between a protein pair by distinguishing the dominant interacting

|

domain pair
(Continued)
19

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Table 3. Continued
20
|

Sr. No# Steps Methods/tools General workflow Description

PPI-MetaGO [160] • PPI-MetaGO constructs a meta-classification model for PPI prediction using • PPI-MetaGO improves PPI prediction by deducing the biases of the base
three types of features: physicochemical features, gene ontology-term features generalizers and exploiting the synergy among various ML algorithms.
and network-based features.
Noor et al.

5 Network DeepDTnet [164] • DeepDTnet first build a heterogeneous network connecting drugs, targets and • Additionally, deepDTnet shows higher robustness in comparison RF, SVMs,
analysis diseases by integrating 15 types of chemical, genomic, phenotypic and cellular k-nearest neighbors and naive Bayes, since it performs well on drugs or
network profiles targets showing high and low connectivity as well as high or low chemical
• DeepDTnet then learn low-dimensional but informative vector representations similarity.
within network for both drugs and targets using a Deep Neural Networks model
for graph representations (DNGR) algorithm
• For any given drug–target pair, it is difficult to verify unobserved evidence that
such a connection is, indeed, nonexistent, or hidden, therefore, deepDTnet
employ the positive unlabeled-learning formulation to low-rank matrix
completion, which is able to infer whether two drugs share a target or not
THN_KRLS [165] • THN_KRLS adds a disease layer to the traditional drug–target interaction • THN_KRLS method performs better than the other existing methods
bipartite graph. when known drug–target interactions are missing in the training data
• From the constructed heterogeneous network, new drug–target interactions can
be inferred with Gaussian kernel functions and the regularized least square
method of the Kronecker product.

6 Hub gene RF algorithm • Li et al. applied RF algorithm to estimate the contribution of differentially • RF has ability efficiently predicts hub genes from pool of differentially
analysis [168, 169] expressed genes in esophageal carcinoma. expressed genes.
• Similarly, Liu et al. used LASSO regression and RF methods for hub gene feature
selection. The author selected final genes based on the classification accuracy of
ML approaches.

7 Prediction of the DeepTox [178] • DeepTox normalizes the chemical structures followed by computation of the • DeepTox supported the automatic learning of features that were similar
mode of action chemical descriptors. to well-established toxicophores identified by expert knowledge and
and toxicity of • The computed descriptors are used in DL methods to predict the toxicity of experience.
compounds chemicals.

Flask-based web • Neural network model is integrated into the web application through which a • Flask-based web application can help researchers to predict the
application [179] user can input a custom testing features data-set containing gene expression mechanism of action and can help them in the discovery of new drugs.
and cell viability levels.
• The output produced is the top classes of drugs, along with their scatter plot.
Genetic • GPAR assists in modeling and predicting mechanism of action through DL. • GPAR offers a more powerful connection of expression signatures and
profile-activity • The users can use GPAR to customize their training sets to train self-defined action mechanism, which could get the high accuracy in modeling action
relationship mechanism of action prediction models, to evaluate the model performances mechanisms and querying signatures, and facilitate drug repurposing
(GPAR) [180] and to make further predictions automatically. opportunities.
8 Integrating ML Kwon et al. [187] • AK-Score utilizes independently trained networks to make predictions and the • AK-Score is a new neural network model for binding affinity prediction
systems for average of those values is considered as the final prediction. of a protein–ligand complex structure
improving Qamar et al. [188] • The author used ML approach to set up a pipeline that scores and ranks • Their findings demonstrates that ML improve the accuracy of
docking biological molecules against the 3CLpro enzymes. structure-based virtual screening by promoting the identification of most
prediction • The RF classifier was used to predict molecule class and RF regression to potential ligands having high accuracy score
reliability determine the molecule’s activity

Hsin et al. [189] • The author combined multiple docking tools and two ML systems to predict the • Integrating this approach with molecular network maps makes it
high-precision binding affinity of redocked ligand poses. possible to address drug safety issues by comprehensively investigating
computational • The first ML system include, not only intermolecular interactions, but also network-dependent effects of a drug or drug candidate.
prediction exploited the physicochemical properties of the ligand as additional features.
approach • The second ML system helps in the selection of most predictive binding modes
for each of the complexes.

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of traditional medicines. Therefore, there is an urgent need to
combine ML approaches with network pharmacology to achieve
better and more accurate outcomes.
This literature review has some limitations that must be kept
in mind for further research. There are some important research
questions that might give important information respect to the
trends and challenges of incorporating ML in network pharma-
cology. For example, we do not specify that which features should
include in ML models to foster the multi-target drug discov-
ery through network pharmacology. Secondly, this study does
not discuss the automated pipeline that integrate network phar-
macology with ML for multi-target drug discovery, as only a
few network pharmacology-based studies used ML at some spe-
cific stages particularly for compound-related target prediction
and diseases-related target prediction. Therefore, further research
should include other analysis including compound–target protein
interaction network analysis as well as compound–target protein–
disease interaction network analysis in order to provide a more
complete understanding of the impact of ML on multi-target drug
discovery. To sum up, further research needs to be done to give
an answer to the aforementioned issues in order to provide other
directions and continue to enlarge the knowledge about ML in
network pharmacology. Besides, with the intention of ensuring the
accuracy of the ML models, it is imperative that further research
includes big data.
CONCLUDING REMARKS AND FUTURE
PERSPECTIVES
The pharmaceutical industry experienced an unprecedented rise
in the cost of developing new drugs. Society needed specific
major improvements in this area as the healthcare industry cur-
rently faces a number of complicated challenges, such as the
skyrocketing costs of both therapies and drugs. Regrading this,
network pharmacology is considered as a new frontier in drug
discovery. Network pharmacology is an in silico approach, inte-
grating bioinformatics and chemoinformatics that helps to build
a network-centric view of drug action. The network pharmacol-
ogy technique lays the most recent scientific groundwork for
evaluating the effectiveness of multi-component, multi-target
compound formulae and investigating the disease treatment of
multiple therapeutic targets. The ongoing implementation of ML
and its tools promises to improve discovery and decision making
in network pharmacology. In the light of the current study, we
thoroughly discuss the backend of ML approaches in supporting
network pharmacology research along with its limitations and
opportunities for the pharmaceutical industry. This assembled
data aimed to discuss the role of ML-based approaches in network
pharmacology for providing more promising treatment options.
We have attempted to cover this vast topic in this review and
hope that it will serve as a reference for clinicians who are eager
to bring advances in network pharmacology for multi-target drug
discovery.
For the future, we believe that the combination of advanced ML
systems with network pharmacology could make an encouraging
progression in multi-target drug discovery. The field is open to
explorations of how active compounds and target proteins can
be used by ML algorithms for concrete drug discovery appli-
cations. Despite the fact that both network pharmacology and
ML has provided many novel targets and unique compounds,
there has not yet been any success story in which compounds
and target proteins identified through network pharmacology
and ML made it to the market for general usage. There is no
doubt that ML will soon bring dramatic improvements in network
Machine learning for synergistic network pharmacology | 21
pharmacology but additional studies are crucial in understudied
areas, generating ML-based pipeline for multi-target drug discov-
ery (Supplementary Figure S1). ML outputs are highly dependent
on the initial values or weights of the network parameters or even
the order in which training examples are presented to the net-
Downloaded from https://academic.oup.com/bib/article/24/3/bbad120/7109956 by Chulalongkorn University, Center for Academic Reso user on 01 December 2023
work. The availability of high-quality, accurate and curated data in
large quantities to train and develop ML models is also challeng-
ing. The requirements for the amounts and accuracy desired are
dependent on the complexity of the data type and the question
to be resolved. Thus, it can be expensive to generate these data
sets. Pre-competitive consortia of pharmaceutical companies and
academic institutions that use appropriate data standards and
have the necessary operational and open data frameworks may
be part of the solution to meet these data demands. Though there
are some unavoidable obstacles and tremendous amount of work
has to be done to incorporate ML tools in network pharmacology,
there is no doubt that in the near future ML will bring revolu-
tionary changes in network pharmacology for multi-target drug
discovery.
Key Points
• Network pharmacology has become an important
research model for multi-target drug discovery. However,
there is a need to improve the predictive performances
in network pharmacology.
• The recent successes of the machine/deep learning
(ML/DL) approaches in drug discovery could be used to
overcome the limitations of network pharmacology.
• With the increasing number of ML available libraries,
toolkits and frameworks, we expect to see additional
research studies and also the examples of ML- or DL-
based production pipelines for network pharmacology in
the near future.
• This review provides an overview of ML and DL
approaches that can be opted to develop multi-target
drugs.
SUPPLEMENTARY DATA
Supplementary data are available online at https://academic.oup.
com/bib.
ACKNOWLEDGEMENTS
Authors would like to acknowledge Integrative Omics and
Molecular Modeling Laboratory, and Biomedical Data Science
Laboratory, Department of Bioinformatics and Biotechnol-
ogy, Government College University, Faisalabad, Pakistan, for
providing necessary support and facilities to conduct this
study.
FUNDING
This research received no specific grant from any funding agency
in the public, commercial, or not-for-profit sectors.
DATA AVAILABILITY
The data underlying this article are available in the article and in
its online supplementary material.
22 | Noor et al.
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