molecules

Review
Machine Learning for Drug-Target
Interaction Prediction
Ruolan Chen 1 ID
, Xiangrong Liu 1 ID
, Shuting Jin 1 , Jiawei Lin 1 and Juan Liu 2, *
1 Department of Computer Science, School of Information Science and Technology, Xiamen University,
Xiamen 361005, China; [email protected] (R.C.); [email protected] (X.L.);
[email protected] (S.J.); [email protected] (J.L.)
2 Department of Instrumental and Electrical Engineering, School of Aerospace Engineering, Xiamen
University, Xiamen 361005, China
* Correspondence: [email protected]




Received: 5 August 2018; Accepted: 27 August 2018; Published: 31 August 2018


Abstract: Identifying drug-target interactions will greatly narrow down the scope of search of
candidate medications, and thus can serve as the vital first step in drug discovery. Considering
that in vitro experiments are extremely costly and time-consuming, high efficiency computational
prediction methods could serve as promising strategies for drug-target interaction (DTI) prediction.
In this review, our goal is to focus on machine learning approaches and provide a comprehensive
overview. First, we summarize a brief list of databases frequently used in drug discovery. Next,
we adopt a hierarchical classification scheme and introduce several representative methods of each
category, especially the recent state-of-the-art methods. In addition, we compare the advantages
and limitations of methods in each category. Lastly, we discuss the remaining challenges and future
outlook of machine learning in DTI prediction. This article may provide a reference and tutorial
insights on machine learning-based DTI prediction for future researchers.

Keywords: drug-target interaction prediction; machine learning; drug discovery

1. Introduction
Most drugs demonstrate efficacy via the in-vivo interactions with their target molecules such
as enzymes, ion channels, nuclear receptors and G protein-coupled receptors (GPCRs). Therefore,
identifying drug-target interactions (DTIs) has become a vital precondition in cognate areas including
poly-pharmacology, drug repositioning, drug discovery, side-effect prediction and drug resistance [1].
The experimentation and confirmation of drug-target pairs have been great hindrances to many drug
researches. On top of that biochemical experiments for undiscovered drug-target interactions involve
significantly costly, time-consuming and challenging work. For instance, it takes around 1.8 billion
dollars for each new molecular entity (NME) [2] as well as an average time span of 9 to 12 years for the
approval of a new drug application (NDA) [3].
Besides the known interactions already stored in various databases, there exist countless unpaired
small molecule compounds that could potentially be discovered and developed into new medications.
Only a small number of drug-target pairs have been experimentally validated in the current data
set. In fact, although there are more than 90 million compounds described in the PubChem database,
a large proportion of interactions still remain to be discovered [4]. Furthermore, the number of truly
innovative drugs approved by regulatory agencies has decreased in recent years, despite the progress
in biotechnology. For instance, it is reported that US Food and Drug Administration (FDA) only
approves approximately 20 novel drugs every year with high investment costs [5]. These large time,
money and resource costs, both human and material, have motivated researchers to constantly develop

Molecules 2018, 23, 2208; doi:10.3390/molecules23092208 www.mdpi.com/journal/molecules

Molecules 2018, 23, 2208 2 of 15

innovative technology for the exploitation of new drugs. Interaction prediction helps to screen new
drugs candidates effectively and efficiently.
Identifying new targets for existing or abandoned drugs, namely drug repositioning, is another
important part in drug discovery. The “multi-target, multi-drug” in place of “one target, one drug”
model has been widely accepted as our understanding of pharmacology deepens [1]. The important
fact is that drugs typically target multiple proteins rather than only one. The anticancer drugs sunitinib
(Sutent) and imatinib (Gleevec) are both concrete evidence. What’s more, drugs may interact with
other proteins in addition to the primary therapeutic targets, namely off-target effects. Off-target effects
are typically considered harmful side effects. However, in some cases, they may be beneficial since
they could lead to unexpected therapeutic effects and provide a new perspective on the molecular
mechanisms of drug side effects. The purpose of drug repositioning is the detection for new clinical
uses for existing drugs. An obvious benefit of drug repositioning is that existing drugs have already
been strictly verified for their safety and bioavailability. Omitting some previously completed steps can
greatly speed up the drug development process. Governments, academic institutions and non-trading
organizations around the world have made more effort into drug repositioning recently which will
effectively facilitate the repositioning research [6].
For all the reasons mentioned above, detecting drug-target interactions is fundamental to both
new drug discovery and old drug repositioning. The known drug-target interactions based on wet-lab
experiments are limited to a very small number. The huge gap between known and unknown
drug-target pairs has prompted interest in DTI prediction. Traditional prediction strategies in vitro
have faced the limitations of time and monetary costs, while recently developed computational or in
silico methods can more efficiently predict potential interaction candidates. Computational methods
have achieved favorable performance in many related bioinformatics fields, such as disease-related
miRNA prediction [7–9], disease genes prediction [10], protein-protein interaction prediction [11]
and protein subcellular location prediction [12]. They greatly narrow the broad scope of research of
experimental DTI validation. Therefore, there is a continuous and urgent demand for the development
of computational techniques on DTI predictions.
Currently, the ligand-based, docking simulation, and chemogenomic approaches are the three
main classes of computational methods for predicting DTIs. Ligand-based methods [13] like
Quantitative Structure Activity Relationship (QSAR) utilize the idea that similar molecules usually
bind to similar proteins. Specifically, these methods predict interactions by comparing a new ligand to
known proteins ligands. However, ligand-based methods perform poorly when the number of known
ligands is insufficient.
As for docking simulation methods [14], the three-dimensional (3D) structures of proteins
are required for simulation hence becoming inapplicable when there are numerous proteins with
unavailable 3D structures. Moreover they cannot be applied to membrane proteins like ion channel
and G-Protein Coupled Receptors (GPCRs) whose structures are too complex to obtain. Docking
simulations usually take significant time and thus it can be especially inefficient.
To address the difficulties of traditional methods, chemogenomic approaches [15] have recently
been performed successfully in drug discovery and repositioning on a large scale. There are four main
types of target frequently involved in DTI prediction, namely protein, disease, gene and side effect.
For the purpose of drug-target pair prediction, these methods integrate both the chemical space of
compounds and the genomic space of target proteins into a unified space: pharmacological space.
Hence, chemogenomic approaches can make full use of abundant biological data that is favorable for
prediction. In such a DTI prediction problem, the major challenge is the scarcity of known drug-protein
interactions and unverified negative drug-target interaction samples. These chemogenomic approaches
can be classified into different categories, such as machine learning-based methods, graph-based
methods and network-based methods [16]. Among all the chemogenomic approaches, machine
learning-based methods have gained the most attention for their reliable prediction results. Most of
these methods generally utilize the chemical and biological features of drugs and targets, and adopt
Molecules 2018, 23, 2208 3 of 15

various machine learning techniques to predict interactions between drugs and targets. Figure 1 is a
branch diagram of recent computational methods for DTI prediction.

Figure 1. Branch diagram of recent computational methods for DTI prediction.

In this review, we focus on machine learning methods applied to DTI prediction. To be specific,
we aim to provide a comprehensive overview on a subclass of chemogenomic approaches exploiting
machine learning frameworks. Compared with those ligand-based methods that also apply machine
learning strategies, the methods discussed in this review can be applicable to target proteins with
insufficient known ligands. Firstly, we summarize a brief list of databases frequently used in drug
discovery. Next, we adopt a hierarchical classification scheme. In particular, we classify the machine
learning methods into two major categories i.e., supervised and semi-supervised methods, and provide
more subclasses. We attempt to introduce several representative methods of each category, respectively.
Furthermore, we present the advantages and disadvantages for methods of each category. Finally,
we will discuss the challenges and further outlook for current machine learning methods in DTI
prediction domain from our point of view.

1. Supervised Learning Methods Both positive labels and negative labels are required in the
training set. Then these labeled samples are used to train the learning models for subsequent
DTI prediction.

• Similarity-based methods The similarities among drugs or among targets are calculated via
various similarity measurement strategies. Similarity matrices can be utilized in various
types of kernel functions:

(i) The nearest neighbor methods: The nearest neighbor methods make predictions
based on the information of the nearest neighbors.
(ii) Bipartite local models: Two local models are firstly trained for drugs and targets
respectively. The final prediction result for each drug-target pair is computed based
on the operation of the two independent prediction scores.
(iii) Matrix factorization methods: Drug-target interaction matrix is factorized into
two latent feature matrices that when multiplied together can approximate the
original matrix.
• Feature vector-based methods The training data is represented as feature vectors. Then some
machine learning models, like Random Forest, can be utilized for prediction based on
these vectors.

2. Semi-Supervised Learning Methods Semi-supervised learning methods make predictions only

based on a small amount of labeled data and a large amount of unlabeled data. To our best
Molecules 2018, 23, 2208 4 of 15

knowledge, there are already some excellent reviews on chemogenomic approaches for DTI
prediction [6,15–19]. Compared to previous works, we focus on the special topic of machine
learning methods used in DTI prediction. Besides, we utilize a hierarchical classification scheme
and summarize several latest prediction methods such as [20–23] which are hardly mentioned
in any previous review. In particular, review [17] is written only from a narrow viewpoint,
namely similarity-based approaches, which are a subclass of machine learning methods.
Surveys [6,15,18,19] all provide a more general and comprehensive overview of chemogenomic
approaches rather than emphasizing machine learning. In recent years, machine learning
has made breakthroughs and attracted a lot of public attention. Discussing state-of-the-art
DTI prediction strategies from this special perspective can demonstrate more methodology
details. Although review [16] also focuses on learning-based methods, its emphasis is only on
supervised learning. In comparison, we provide more detailed sub-classes and introduce newly
developed methods after review [16] was published. The rest of this article is organized as follows:
The “Databases” section describes current available data sources for DTI prediction research.
The “Methods” section briefly introduces several representative machine learning methods via a
hierarchical classification scheme. Then we discuss advantages and limitations of methods in
each category as well as remaining challenges. Finally, the “Conclusions and Outlook” section
makes a future perspective for machine leaning in DTI prediction.

2. Databases
Data mining and utilization based on the existing bioinformatics databases is a significant
methodology for drug discovery. With the development of molecular biology, abundant information
about drugs and targets has accumulated. Thus, it is necessary to establish databases for managing
and maintaining the data. There exist a number of different professional databases involving potential
cellular targets for various families of chemical compounds up to now. A large portion of them are
publicly available. Moreover, the data size is increasing owing to the contributions of researchers
from around the world. As more information about drugs and targets is collected, there are more
opportunities for drug discovery research. To a certain degree, these databases have promoted the
development of latest methodologies for drug discovery. In Table 1, we list frequently used databases,
their web servers and brief descriptions. Table 2 shows the statistics of the number of compounds,
targets and compound-target interactions in these databases. Note that not all databases provide
complete information in their databases and published papers.
Some of these databases are being updated frequently, such as DrugBank, KEGG, and STITCH
and so on, while the data in other databases has remained almost the same for several years, such as
SuperPred which was last updated in April 2014. It is, however, encouraging that more new databases
and easy-to-use web servers have been recently established. On one hand, the existing databases
provide plentiful data sources of drug space and target space. It is time for the researchers to make
efforts to integrate more different types of heterogeneous data. On the other hand, current databases
do not involve any non-interaction information. This common drawback has limited the prediction
result of supervised learning methods. Thus it would be meaningful to make public both interactions
and non-interactions between drugs and targets in the future.
Molecules 2018, 23, 2208 5 of 15

Table 1. Databases supporting drug discovery methods.

Database and URL Brief Descriptions

An encyclopedia of genes and genomes for both
KEGG [29]
functional interpretation and practical application of
http://www.genome.jp/kegg
genomic information.
BRENDA [30] The main enzyme and enzyme-ligand information
http://www.brenda-enzymes.org/ system.
A database for information on chemical substances
PubChem [31] and their biological activities involving three
https://pubchem.ncbi.nlm.nih.gov/ inter-linked databases, i.e., Substance, Compound
and BioAssay.
Therapeutic Target Database providing
TTD [32] comprehensive information about the drug resistance
http://bidd.nus.edu.sg/group/ttd/ttd.asp mutations, gene expressions and target combinations
data.
Consisting of two parts information involving
DrugBank [33] detailed drug data (i.e., chemical, pharmacological
http://www.drugbank.ca and pharmaceutical) and drug target information (i.e.,
sequence, structure, and pathway) respectively.
SuperTarget [34] A database integrating drug-related information with
http://bioinf-apache.charite.de/supertarget more than 330,000 compound-target protein relations.
Data resource for molecule structures and
ChEMBL [35]
molecule-protein interactions collected from the
https://www.ebi.ac.uk/chembldb
primary published literature on a regular basis.
STITCH [36] Repository of known and predicted chemical-protein
http://stitch.embl.de/ interactions.
MATADOR [37] A database of protein-chemical interactions including
http://matador.embl.de/ as many direct and indirect interactions as possible.
BindingDB [38]
A public database of protein-ligand binding affinities.
http://www.bindingdb.org/bind
TDR targets [39] A chemogenomics resource for neglected tropical
http://tdrtargets.org/ diseases.
SIDER [40] Serving information on marketed medicines and their
http://sideeffects.embl.de/ recorded adverse drug reactions.
Collections of available data derived from small
ChemBank [41]
molecules and small-molecule screens and resources
http://chembank.broad.harvard.edu/
for studying their properties.
DCDB [42] The Drug Combination Database for collecting and
http://www.cls.zju.edu.cn/dcdb/ organizing known examples of drug combinations.
Cancer Drug Resistance Database of 148 anticancer
CancerDR [43]
drugs and their effectiveness against around 1000
http://crdd.osdd.net/raghava/cancerdr/
cancer cell lines.
The first Antifungal Synergistic Drug Combination
ASDCD [44] Database including published synergistic antifungal
http://asdcd.amss.ac.cn/ drug combinations, targets, indications, and other
pertinent data.
SuperPred [45]
Resource of compound-target interactions.
http://prediction.charite.de/
Molecules 2018, 23, 2208 6 of 15

Table 2. The statistics of the number of compounds, targets and compound-target interactions in the
databases covered in the review.

The Number of
The Number of
Databases The Number of Targets Compound-Target
Compounds
Interactions
KEGG 18,380 26,885,475
BRENDA 7341
PubChem 96,479,316 68,868
TTD 34,019 3101
DrugBank 11,682 26,889 131,724
SuperTarget 195,770 6219 332,828
ChEMBL 2,275,906 12,091
STITCH 500,000 9,600,000 1,600,000,000
MATADOR 775
BindingDB 652,068 7082 1,454,892
TDR targets 2,000,000 5300
SIDER 5868 1430 139,756
ChemBank 1,700,000
DCDB 904 805
CancerDR 148 116
ASDCD 105 1225 210
SuperPred 341,000 1800 665,000

3. Methods
In the era of big data, machine learning methods are designed to generate predictive models
based on some underlying algorithm and a given big data set. For biological and biomedical
research, machine learning plays a pivotal role in filtering large amounts of data into patterns [24–27].
The general machine learning workflow in DTI prediction can be divided into three steps. First,
preprocessing the input data of the drug and the target; second, training the underlying model based
on a set of learning rules; third, utilizing the predictive model to make predictions for a test data set.
From our research, study [28] is the first work that applies machine learning to protein-chemical
interaction prediction. This work establishes a SVM analysis framework of amino acid sequence data,
chemical structure data and mass spectrometry data. This pioneering study has inspired subsequent
studies. Machine learning for drug discovery has become a field of long-standing and growing interest
since then.
For simplicity, we classify machine learning methods for drug-target interaction prediction
into two major categories, i.e., supervised learning and semi-supervised methods. Specifically,
the supervised learning methods can be further classified into two sub-classes including
similarity-based methods and feature-based methods.

3.1. Supervised Learning Methods

Supervised learning methods are applied to train the learning model and identify patterns
when labels are available. For the DIT prediction problem, known drug-target interactions are
labeled as positive samples and the rest are labeled as negative ones. Next, these labels are used
to train the model for subsequent interaction predicting. In fact, those drug-target pairs without
explicit interaction information may correspond to unknown or missing interactions rather than
Molecules 2018, 23, 2208 7 of 15

non-interactions. In general results of non-interactions between drugs and targets are not published.
Methods of this category regard all the unknown drug-target interactions as non-interaction despite
inaccuracy. In the section, we will review the supervised methods proposed so far in two categories,
i.e., similarity-based methods and feature-based methods.

3.1.1. Similarity-Based Methods

A key underlying assumption of similarity-based machine learning methods is the
“guilt-by-association” assumption, that is, similar drugs tend to share similar targets and vice versa.
In this kind of approach, the similarity among drugs or among targets is computed by various similarity
measures. The constructed similarity matrices define several types of kernel functions.
• The Nearest Neighbor Methods
The nearest neighbor methods generally adopt relatively simple similarity functions. Researchers
often integrate these methods with some other approaches to help predict new drugs or targets, such as
models in paper [46,47]. In the early stage, study [48] proposed two exploratory approaches, namely
the nearest profile method (NN) and the weighted profile method. The nearest profile method follows
the key concept that similar drugs or targets tend to be close in the network. This method was used
in [49] as the baseline. In contrast, the weighted profile method utilizes the similarities of all the
other drugs and targets and then adopts a weighted average. However, these methods show poor
performance in the case when targets bound to similar drug share low sequence similarity or vice versa.
In the studies [23,50] by Zhang et al., methods that make drug-drug pair predictions based on
neighbors were developed. These studies further extended the classic neighbor recommender method
to the integrated neighborhood-based method (INBM). In simple terms, neighbor recommender
method generally uses the weighted average information of neighbors for prediction. INBM is an
ensemble model that integrates several neighborhood-based models for a robust prediction. For each
drug-drug pair, three commonly used formulas, namely Jaccard similarity, Cosine similarity and
Pearson correlation similarity, are used to calculate similarity score.
Another novel methodology in this category is Similarity-Rank-based predictor (SRP) [51].
Two indices, i.e., tendency index and inverse tendency index, are computed to construct a SRP.
To be specific, the former represents the likelihood that each drug–target pair tends to interact, while
the latter measures the tendency that each drug–target pair does not interact. The calculation formulas
involve both similarity and similarity rank. Then an interaction likelihood score is computed as
the likelihood ratio of the two indices. This method can generate two interaction likelihood scores,
one from the drug side and the other from the target side. The final prediction score is the average of
the two scores. The clear advantage of SRP is that it is a lazy and non-parametric model without the
requirements of an optimization solver, prior statistical knowledge as well as tunable parameters.
In recent years, other new similarity-based methods have been proposed one after another,
such as rule-based inference. Due to the limitation of the previous topology-based methods,
a similarity-based deep learning method [52] merges the similarity measure with two rule-based
inference methods. In other words, drug-based similarity inference (DBSI) and target-based similarity
inference (TBSI) [48,53] are adopted to discover the drug-target interactions with the similarities.
Though it is flexible to assemble any kernel functions, the method cannot predict new drugs or targets.
Note that most of similarity measures only utilize some important drug-related or disease-related
properties to perform drug-disease prediction and ignore the known drug-disease interaction
information [54]. Some researchers have proposed new similarity measures. Luo et al. [54] have
designed a comprehensive similarity measure. In order to improve traditional similarity measures for
drug-disease prediction, the comprehensive similarity measure has integrated drug or disease feature
information with known drug–disease interactions. The similarity measure can be broken down into
three steps. In the first step, drug similarity and disease similarity are calculated based on drug-related
properties or disease-related properties respectively. In the second step, these similarity values are
Molecules 2018, 23, 2208 8 of 15

adjusted by a logistic function based on the analysis and evaluation results. In the last step, a weighted
drug network can be established for the drug similarity. The edge weight represents the number of
common diseases between corresponding drugs. Then a cluster method, ClusterONE, is applied to
identify potential drug clusters. Similarity between drugs belonging to the same cluster is enhanced
and thus comprehensive drug similarity is obtained. Disease similarity can be improved in the same
way as for drugs.
• Bipartite Local Models
Bipartite local models (BLMs) firstly generate two independent prediction for drugs and targets
respectively. The final prediction result is then obtained by aggregating the two prediction scores.
The concept of BLM was first introduced in the pioneering work by Bleakley and Yamanishi [49].
This method can transform the drug-target interaction prediction problem into a binary classification
problem. More specifically, a local model is trained for drugs based on chemical similarity. Another
one is trained for proteins based on sequence structure. Therefore, two SVM classifiers can generate
two independent prediction results from the drug or target side respectively. Final prediction result for
each drug-target pair is computed based on the average of these two independent prediction scores.
Analogously, another method [55] developed a regularized least square classifier introducing two
algorithms, called RLS-avg and RLS-kron. In particular, Regularized Least Squares (RLS-avg) utilizes
kernel ridge regression to perform prediction. While in RLS-kron, all pairs of drugs and targets are
combined into one to make Kronecker product, bringing the runtime down greatly.
Considering the limitation of the BLM-based methods above of predicting new drug or target
without any known interactions available, Mei et al. [46] extended existing BLM by adding a
preprocessing to infer training data from neighbors’ interaction profiles. The method is called Bipartite
Local Models with Neighbor-based Interaction Profile Inferring (BLM-NII). BLM-NII involves RLS-avg
algorithm and is proven to be effective in new candidate problem.
• Matrix Factorization Methods
Matrix factorization methods are typically used in recommendation systems to find potential
user-item interactions. The DTI prediction can be regarded as a matrix completion problem that aims
to look for missing interactions. Therefore, drug-target interaction matrix can be factorized into two
other matrices that when multiplied together can approximate the original matrix.
Kernelized Bayesian Matrix Factorization with Twin Kernels (KBMF2K) [56] is the original method
that introduced matrix factorization to DTI prediction. Following some previous approaches, KBMF2K
defines two kernel matrices only based on chemical similarity between drug compounds and genomic
similarity between target proteins. It combines Bayesian probabilistic formulation, matrix factorization
and binary classification for prediction problem.
Another study adopting probabilistic formulations is Probabilistic Matrix Factorization (PMF) [57].
PMF is distinguished greatly from KBMF2K by its independence of drug or target similarity
matrices. Furthermore, the study presented the active learning (AL) strategy along with probabilistic
matrix factorization.
Zheng et al. [58] proposed an extension of weighted low-rank approximation from one-class
collaborative filtering (CMF), namely Multiple Similarities Collaborative Matrix Factorization
(MSCMF). MSCMF integrates multiple similarity matrices, including chemical structure similarity,
genomic sequence similarity, ATC similarity, GO similarity and PPI network similarity. Weights
over the matrices are estimated to select similarities automatically. This strategy improves predictive
performance in the experiment. Drugs and targets are projected into low-rank matrices. Then weights
over similarity matrices are estimated using an alternating least squares algorithm. However, regardless
of its performance, under this data integration strategy, a large amount of information may be lost,
thus leading to sub-optimal solution.
Molecules 2018, 23, 2208 9 of 15

The method developed by Ezzat et al. [59], employed two matrix factorization methods (i.e.,
GRMF and WGRMF). It was revealed in previous work [60] that data usually lies on or nears to the
low-dimensional and non-linear manifold. Therefore, GRMF and WGRMF perform manifold learning
implicitly by means of graph regularization. In addition, a preprocessing step (WKNKN) was applied
to new drug or target prediction by transforming all the 0’s in the original drug-target matrix into
interaction likelihood values. This important step distinguishes this method from other work that
regards all the 0’s of given drug-target matrix as non-interaction roughly, and thus enhances the
prediction results.

3.1.2. Feature Vector-Based Methods

Generally, similarity-based prediction algorithms do not take heterogeneous types and interactions
defined in semantic networks into consideration. In addition, it may be difficult to add the long indirect
connections between two nodes. Therefore, feature vector-based methods have been utilized for DTI
prediction. The input of feature vector-based methods is drug-target pairs represented by fixed-length
feature vectors. The feature vectors are encoded by various properties of drugs and targets.
In the systematic approach [61], chemical descriptors are calculated using DRAGON
program (http://www.talete.mi.it/index.htm). Finally, each drug is represented as a set of
1080 descriptors, including constitutional descriptors, topological descriptors, 2D autocorrelations,
eigenvalue-based indices and so on. Likewise, each protein is represented by a set of structural and
physicochemical descriptors via PROFEAT WEBSEVER (http://jing.cz3.nus.edu.sg/cgi-bin/prof/prof.
cgi). The descriptors involve Amino acid composition descriptors, Dipeptide composition descriptors,
and Autocorrelation descriptors and so on. Then each protein sequence with changeable length can
be transformed into a standard feature vector of 1080 dimensions. Hence, a set of 2160-dimensional
feature vectors for each drug-target pair can be constructed. Subsequent prediction step performs
Random Forest (RF) algorithm which introduces random training set (bootstrap) and random input
vectors into the trees. The comprehensive framework shows its robustness against the over fitting
problem and performs more efficiently for a large-scale data set in experiments.
In order to integrate diverse information from heterogeneous data sources, a method named
DTINet was proposed by Luo et al. [20]. Through DTINet, a low dimensional feature vector that
accurately explains the topological properties of each node in the heterogeneous network is first
learned. In the further step, DTINet applies inductive matrix completion to best project drug space
onto protein space.
Due to the fact that DTINet separates features and may result in loss of the optimal solution,
Wan et al. [21] created a new framework called neural integration of neighbor information for DTI
prediction (NeoDTI). The inspiration of NeoDTI came from convolution neural networks (CNNs).
It integrates the neighbor information in heterogeneous network. After extracting the complex hidden
features vectors of drugs and targets, NeoDTI automatically learns topology-preserving representations
to achieve superior prediction performance.
The pioneering effort in [62] introduced a two-layer undirected graphical model, namely restricted
Boltzmann machine (RBM), into a large-scale drug-target interaction prediction. There are no
intra-layer connections in these layers. What’s more, RBM model is trained via a practical learning
algorithm, i.e., Contrastive Divergence (CD). Where the method significantly outperforms other
existing approaches is in that it can predict different types of DTIs on a multidimensional network.
In other words, the method can identify binary DTIs as well as their corresponding types of interactions,
including relationships and drug modes of action.
In the paper published by Fu and cooperators [63], a state-of-the-art machine learning model was
constructed based on meta-path-based topological features. Two measures of topological features are
calculated, including the number of path instances between nodes and a normalization process to it.
Given features, a Random Forest algorithm is used as supervised classification. Furthermore, intrinsic
Molecules 2018, 23, 2208 10 of 15

feature ranking algorithm embedded in Random Forest selects the important topological features for
better prediction. This framework has shown precise predictability.

3.2. Semi-Supervised Learning Methods

Considering the negative sample selection has a great influence on the accuracy of DTI
prediction results, some researchers have proposed semi-supervised methods to address the problem.
These methods use only a small amount of labeled data and a large amount of unlabeled data.
Semi-supervised methods typically use the labeled data to infer labels for unlabeled data. On the other
hand, the unlabeled data can also help provide insights into the structure of training set.
Having no use of negative samples, study [64] first employed a manifold Laplacian regularized
least square (LapRLS) based on the BLM concept. Furthermore, an extension of the standard
LapRLS, namely NetLapRLS, was proposed. NetLapRLS integrates information from chemical space,
genomic space and drug-protein interaction for a new kernel. These semi-supervised methods have
achieved encouraging results than using the labeled data alone. However, it is time-consuming when
implementing them on a large scale.
Another method is designed for both semi-supervised and unsupervised settings. Ma et al. [22]
presented a new framework to learn accurate and interpretable similarity measures when labels
are scarce. This framework constructs a set of Graph Auto-Encoder (GAE)-based models and
integrates multi-view drug similarities. Besides, an attentive mechanism is used for view selection and
better interpretability.

3.3. Discussion
Each machine learning model possesses its unique advantages as well as disadvantages. Note
that just as the popular concept in computer science, namely “no free lunch theorem” [65], machine
learning methods are context-specific. Therefore, in this review we can only evaluate the advantages
and disadvantages of each method category based on DTI prediction context.
A number of supervised models have been already proven feasible for DTI prediction. However,
most supervised methods simply regard all the unlabeled drug-target pairs as negative samples
and thus generate inaccurate predictive results. What’s more, each similarity-based method
has its limitation when extending to large a data set because of high complexity of similarity
matrices computation.
Consider the three sub-classes of similarity-based methods respectively. Although the nearest
neighbor methods generally apply relatively simple similarity functions, most of them construct
neighborhoods only based on first-order similarity and do not involve the transitivity of similarity [66].
A key advantage of bipartite local models is that they process much fewer drug-target pairs, and thus
they have much lower complexity than global models. Nevertheless, bipartite local models cannot
handle the scenario that both drugs and targets are not involved in the training set unless combined
with other methods. According to the experiment result in [19], matrix factorization methods generally
have more superior performance than other methods including the nearest neighbor models and
bipartite local models.
A small number of known drug-target interactions results in an imbalanced dataset. As an
effective solution for imbalanced datasets, semi-supervised learning uses only a small amount of
labeled data with a large amount of unlabeled data and generates more reliable prediction than
supervised one.
In addition to the aforementioned single machine learning methods, we also have introduced
several ensemble methods [61,63]. A better and robust prediction generally results from the biases
trade-off of each single method. Generally, ensemble methods can combine different learning models.
For more ensemble methods applied to drug-target interaction prediction task, please refer to [67–69].
Generally, machine learning has achieved favorable performance in DTI prediction. Nonetheless,
a number of challenges still remain. Above all, recently, some researchers have emphasized that
Molecules 2018, 23, 2208 11 of 15

predictive models based on machine learning are usually established and evaluated with overly
simplified settings. Prediction results under such experiment settings may be over optimistic and
deviate from the real case. Particularly, most of machine learning methods simply regard drug-target
interaction as an on-off relationship and ignore other vital factors like molecule concentrations and
quantitative affinities. Pahikkala et al. [24] have pointed out four factors having significant impact
on prediction results, including problem formulation, evaluation data set, evaluation procedure and
experimental setting. Considering the binding affinities and dose-dependence of drug-target pairs,
the DTI prediction problem should be formulated as a regression or rank prediction problem rather
than a standard binary classification problem. The second challenge is the imbalanced dataset problem.
Due to the small number of known drug-target pairs, the current dataset is imbalanced. Some models
like decision trees and SVMs, have a great bias for recognizing the majority class and thus result
in poor performance [16]. Thirdly, most machine learning models possess “poor interpretability”
properties. In other words, it is difficult to understand the underlying drug mechanism of action from a
biological perspective. Note that in most case, it is easier to explain relatively simple models. This case
is consistent with one of the “rules of thumb” [70], that is “simple is often better”. Nonetheless,
for most current state-of-the-art approaches achieving high DTI prediction accuracy, such as deep
learning methods, it is difficult to interpret them from a pharmacology perspective. Last but not
least, there are still no uniform evaluation metrics special for DTI prediction. Previous studies have
adopted some common evaluation metrics in bioinformatics [71], such as sensitivity, specificity, Area
Under the Precision-Recall (AUPR) curve and Area under the ROC curve (AUC). The fact is that if
the sensitivity increases, the specificity decreases. Considering the limitation of using sensitivity or
specificity alone, AUPR and AUC may be better choices in evaluation tasks. In the currently accessible
datasets, the number of unknown samples is much more than the known ones, and thus false positives
should be weighed more. AUPR can reduce the impact of false positive data on evaluation results
as possible [72], and AUC is insensitive to imbalance dataset [73]. Thus both AUPR and AUC are
generally adequate metrics for evaluating the performance of machine learning-based methods.

4. Conclusions and Outlook

DTIs contribute to the selection of potential drugs and thus effectively reduce the scope of research
for biochemical experiments. Besides, they can provide deep insights into the side effects and the
mechanism(s) of action of drugs. Hence, DTI prediction is a vital prerequisite for drug discovery.
In fact, a number of public available databases have been established and promoted the development
of innovatory DTI prediction strategies.
In this review, we focus on machine learning-based methods integrating chemical space and
genomic space. We summarize the databases and machine learning methods frequently used in DTI
prediction. In particular, we focus on several state-of-the-art predictive models appearing in recent
years. We adopt a hierarchical classification scheme. We classify machine learning methods into two
major categories: supervised and semi-supervised methods, and provide more subclasses.
Machine learning will be promising in DTI prediction for the next several years. However, there
is still much room for improvement. Hence, we conclude with some advice as a reference for the
future researchers.
Firstly, ensemble approaches combine multiple independent classifiers into one model and
typically achieve a better prediction results. Next, semi-supervised learning is a powerful tool for
addressing the imbalanced dataset problem. However, only a small number of semi-supervised
learning methods have been proposed recently. Hence, the research on semi-supervised learning
methods needs more attention. Furthermore, note the fact that drug-target pairs involve binding
affinities and dose-dependence. It is more practical and meaningful to study new regression methods
for DTI prediction problem. The using of quantitative bioactivity data will lead to a more accurate and
reliable predictive result. Finally, with the development of high throughput biotechnology, the available
Molecules 2018, 23, 2208 12 of 15

data has been growing quickly recently. It is time for further machine learning technology to take full
advantage of more different types of heterogeneous data.

5. Key Points
1. Identifying drug-target interactions is the vital first step in drug discovery research.
2. A number of existing professional databases serve known data resources for DTI prediction and
thus promote the drug discovery.
3. Machine learning-base methods are generally effective and reliable for DTI prediction.
4. Different machine learning methods have their merits and demerits. Hence, it is essential to
choose appropriate methods or assemble models for special prediction tasks.
5. A more effective prediction model can be established by integrating more heterogeneous data
sources of drugs and targets.
6. In reality, DTI prediction is a regression problem with quantitative bioactivity data.

Author Contributions: Conceptualization, R.C.; Writing-Original Draft Preparation, R.C.; Writing-Review &
Editing, R.C., X.L., S.J. and J.L. (Jiawei Lin); Funding Acquisition, X.L.; Supervision, J.L. (Juan Liu).
Funding: This research was funded by the National Natural Science Foundation of China grant numbers [61472333,
61772441, 61472335, 61425002], Project of marine economic innovation and development in Xiamen grant number
[16PFW034SF02], Natural Science Foundation of the Higher Education Institutions of Fujian Province grant
number [JZ160400], Natural Science Foundation of Fujian Province grant number [2017J01099], President Fund of
Xiamen University grant number [20720170054], and the National Natural Science Foundation of China grant
number [81300632].
Acknowledgments: We would like to thank all authors of the cited references.
Conflicts of Interest: The authors declare no conflicts of interest.

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