International Journal of

Molecular Sciences

Review
Recent Advances in Machine-Learning-Based
Chemoinformatics: A Comprehensive Review
Sarfaraz K. Niazi 1, * and Zamara Mariam 2

1 College of Pharmacy, University of Illinois, Chicago, IL 61820, USA

2 Zamara Mariam, School of Interdisciplinary Engineering & Sciences (SINES), National University of
Sciences & Technology (NUST), Islamabad 24090, Pakistan; zmariam.msbi21rcms@student.nust.edu.pk
* Correspondence: niazi@niazi.com; Tel.: +1-312-297-0000

Abstract: In modern drug discovery, the combination of chemoinformatics and quantitative structure-
activity relationship (QSAR) modeling has emerged as a formidable alliance, enabling researchers to
harness the vast potential of machine learning (ML) techniques for predictive molecular design and
analysis. This review delves into the fundamental aspects of chemoinformatics, elucidating the intri-
cate nature of chemical data and the crucial role of molecular descriptors in unveiling the underlying
molecular properties. Molecular descriptors, including 2D fingerprints and topological indices, in
conjunction with the structure–activity relationships (SARs), are pivotal in unlocking the pathway
to small-molecule drug discovery. Technical intricacies of developing robust ML-QSAR models,
including feature selection, model validation, and performance evaluation, are discussed herewith.
Various ML algorithms, such as regression analysis and support vector machines, are showcased in
the text for their ability to predict and comprehend the relationships between molecular structures
and biological activities. This review serves as a comprehensive guide for researchers, providing an
understanding of the synergy between chemoinformatics, QSAR, and ML. Due to embracing these
cutting-edge technologies, predictive molecular analysis holds promise for expediting the discovery
of novel therapeutic agents in the pharmaceutical sciences.

Keywords: QSAR; QSPR; chemoinformatics; small molecules; AI/ML; molecular descriptors;

biological activity; SAR; predictive modeling; computational validation
Citation: Niazi, S.K.; Mariam, Z.
Recent Advances in
Machine-Learning-Based
Chemoinformatics: A
1. Introduction
Comprehensive Review. Int. J. Mol.
Sci. 2023, 24, 11488. https://doi.org/
In 1998, the term “chemoinformatics”, coined by Frank K. Brown, was intended to
10.3390/ijms241411488
hasten drug discovery and development; however, now, chemoinformatics is crucial in
biology, chemistry, and biochemistry. The general process of drug discovery took 12 to
Academic Editor: Hanoch Senderowitz
15 years and involved investments of around $500 million in 1998. New developments in
Received: 9 June 2023 machine learning (ML) and artificial intelligence (AI) have revolutionized chemoinformatics
Revised: 30 June 2023 and drug discovery to a great degree. Market revenue for small-molecule drug discovery
Accepted: 12 July 2023 was $75.96 billion in 2022 and is projected to hit around $163.76 billion by 2032 [1,2].
Published: 15 July 2023 In contrast to previously well-established statistics, mathematics, and physics-based
stand-alone models, ML has introduced a paradigm shift, allowing computers to analyze
data and draw conclusions and predictions without relying solely on explicit rules or
predefined mathematical equations. These algorithms can discover complex patterns
Copyright: © 2023 by the authors. and relations in 3D chemical structures and biological activity data, adaptively adjust
Licensee MDPI, Basel, Switzerland. their models based on feedback, and generalize from training examples to make accurate
This article is an open access article
predictions on unseen data. This data-driven approach has opened new avenues for
distributed under the terms and
optimizing drug–target interactions; empowering target-based drug discovery, chemical
conditions of the Creative Commons
library screening, molecular modeling, mechanics, and dynamics; prioritizing potential
Attribution (CC BY) license (https://
drug candidates; and predicting possible toxicological responses of biologics with improved
creativecommons.org/licenses/by/
accuracy and efficiency. This review discusses the current state of research, the potential
4.0/).

Int. J. Mol. Sci. 2023, 24, 11488. https://doi.org/10.3390/ijms241411488 https://www.mdpi.com/journal/ijms

Int. J. Mol. Sci. 2023, 24, 11488 2 of 15

integration of ML-driven chemoinformatics tools, techniques in drug discovery, and the

challenges and limitations of using these methods. Through a comprehensive analysis of
recent studies and developments, we aim to provide insights into the exciting possibilities
this integration holds for the future of small-molecule drug discovery and design.

2. Exploration of Chemoinformatics
At the intersection of chemistry and informatics, chemoinformatics has emerged
as a potent field in drug discovery, employing inductive learning to predict chemical
phenomena [3,4]. With the exponentially increasing accessibility of chemical data, the
application of ML in chemoinformatics has revolutionized the way researchers now explore,
analyze, and predict the properties and activities of molecules. Compared to a few decades
ago, it has expedited the process by many folds. It focuses on molecular engineering,
molecular manipulation, library design, compound database searching, chemical space
exploration, molecular graph mining, pharmacophore, and scaffold analysis [5–9].

3. Fundamentals of Chemoinformatics
ML models perform prediction tasks based on chemical training data provided in
the form of mathematical equations or a numerical representation. This transformation of
compound structures into machine-learning-ready chemical data involves a complex, mul-
tilayer computational process. The process encompasses descriptor generation, molecular
graphs, fingerprint construction, similarity analysis, chemical space searching, molecular
dynamic simulations, etc. Each layer is interwoven with the preceding layers, significantly
influencing the interpretation of the chemical data by the machine learning models and
enhancing their predictive capabilities.

3.1. Data Mining and Chemical Databases

Training ML models requires chemical data, and chemoinformatics involves using
chemical databases to store and retrieve chemical information. These databases enable
searching for specific molecules or analyze large chemical datasets. The training of mod-
els relies heavily on managing and utilizing chemical databases that store vast amounts
of chemical information, including compound structures, biological activities, and other
relevant physiochemical properties. These databases facilitate data mining, knowledge
discovery, and information retrieval for target prediction. Specialized databases of natu-
rally existing compounds, including LOTUS [10], COCONUT [11], SuperNatural-II [12],
NPASS [13], SymMap [14], TCMSP [15] and TCMID [16] provide valuable resources. These
databases contain comprehensive information on compound structures, molecular physico-
chemical properties, and molecular descriptors.
Utilizing the known structures of these compounds, abductive techniques based on
structural similarities can be leveraged to convey knowledge regarding the mechanism.
Various similarity scores, as mentioned before, can be computed, considering the similarity
of 1D structures (e.g., SMILES- or SELFIES-based similarity [17]), 2D structures (e.g., 2D
fingerprints or topological similarity), and even 3D structures (e.g., 3D geometric shape-
based similarity). Previous studies have identified several metrics suitable for molecular
similarity calculations, including the Tanimoto index, Manhattan distance, Dice index,
overlap coefficient, cosine coefficient, and Soergel distance [18–20]. Furthermore, chemical
bioactivity and structural data can be acquired from drug databases like ChEMBL [21], Bind-
ingDB [22], DrugBank [23], Inxight [24], and Protein Data Bank [25]. Despite the availability
of extensive databases, utilizing machine learning and deep learning techniques offers
significant potential to enhance the creation of molecules and focused libraries, enabling
the discovery of potent bioactive compounds through targeted design and generation
strategies in QSAR studies.
Generative models like recurrent neural networks (RNN) have been employed to
generate novel chemical structures predicted to have desirable properties, such as high
potency or low toxicity. RNN models have been previously used to generate focused
Int. J. Mol. Sci. 2023, 24, 11488 3 of 15

molecule libraries and have implicitly learned chemical knowledge to create molecules with
combined characteristics of both bioactive natural products and synthetic compounds, such
as DeepMGM. Besides this, generative models have been used for inverse QSAR/QSPR,
which involves generating molecules that meet specific target properties.
The DeepMGM model was trained using drug-like molecules and produced a general
model (g-DeepMGM) capable of generating scaffold-focused libraries. A target-specific
model (t-DeepMGM) for the cannabinoid receptor 2 (CB2) using transfer learning was also
developed. A discriminator was incorporated into DeepMGM for in silico molecular design
and testing. The generated molecule XIE9137 was identified as a potential CB2 allosteric
modulator, highlighting the effectiveness of deep learning in de novo molecular design
and chemical library generation [26,27].

3.2. Chemical Data Representation

Advancements in ML modeling and the availability of a vast pool of chemical and bio-
logical data have led to a dire need for data to be translated into computer-understandable
form before models are trained on them. Chemical data representation can be empirical,
molecular, and structural data represented in molecular graphs, fingerprints, descriptors,
etc. [28,29]. A multivariate random forest model generated for genomic characterization
was trained on genomic sequencing data given in numerical representation in one study [30].
In another, a Naïve Bayesian (NB) model was developed on numeric-based activity data,
representing antagonists’ binding on estrogen receptors [31]. An ML-based model was
trained on 31 chemical numerical datasets obtained from Merck to predict the properties
of small compounds based on ADMET (absorption, distribution, metabolism, excretion,
and toxicity) [32]. Similarly, molecular fingerprint data have also been used to train such
models for ADMET properties prediction. NB and QSAR integrated models have been used
to predict active compounds against human immunodeficiency virus type-1 trained on
descriptors including extended-connectivity fingerprint data [33]. Furthermore, the graph
neural networks (GNNs) function with the graph structure data of 3D molecules and have
been used to identify potential drug molecules [34]. Besides the choice of representation,
data augmentation, and pre-processing, the twin curse of dimensionality and collinearity
must be tackled.
When encountered in these data representations and modeling approaches, the twin
curse of dimensionality and collinearity is addressed through principal components analy-
sis (PCA), partial least squares (PLS), and other available techniques. The data often involve
many genomic or chemical descriptors in genomic characterization and small-molecule
property prediction. This high-dimensional feature space can lead to overfitting, decreased
model interpretability, and increased computational complexity. In studies involving ac-
tivity data, binding assays, or molecular fingerprints, collinearity can arise from strong
correlations or dependencies among these input variables. Highly correlated variables can
introduce redundancy and multicollinearity issues, leading to unstable model estimates
and difficulties in interpreting the contributions of individual variables.
To address these challenges, dimensionality reduction techniques such as feature
selection, feature extraction, data regularization, penalization, and genetic algorithms
can help mitigate these issues by imposing constraints and encouraging sparsity. The
principal components analysis (PCA) and the partial least squares (PLS) methods generally
transform massive datasets with correlated variables into smaller uncorrelated ones. PCA
has been used to explore complex datasets in QSAR and dimensionality reduction. A
study investigating PCA’s different applications in QSAR uses a dataset including CCR5
inhibitors. PCA has been used to detect outliers in the datasets, as well. The original data
matrix from a different investigation was examined using PCA, in which molecules are
represented by several predictor variables (molecular descriptors). PCA has also been used
to design features for estrogen receptor binding prediction. Furthermore, observations
revealed enhanced performance in therapeutic activity predictions against a diverse range
of pharmacological protein targets identified by the kernel–principal components (kernel-
Int. J. Mol. Sci. 2023, 24, 11488 4 of 15

PCA) analysis and a nonlinear PCA variation, surpassing the predictive capabilities of
LASSO regression.
Similarly, the partial least squares (PLS) method has been employed to discern sig-
nificant structural patterns that contribute to the biological activity of a molecule. The
efficiency and accuracy of PLS in combination with unsupervised dimensionality reduction
techniques surpass the approach of explicitly combining unsupervised dimensionality
with multivariate regression. PLS is also widely utilized in the field of 3D-QSAR model-
ing [6,35,36].

3.3. Molecular Descriptors

Molecular descriptors are quantifiable representations that capture chemical com-
pounds’ structural, physicochemical, and biological properties. These descriptors are quan-
titative measures used for similarity analysis, virtual screening, and predictive modeling.
Chemical molecular descriptors are categorized as 0D, 1D, 2D, 3D, and 4D (Table 1) [37–40].

• 0D Descriptors: These are constitutional or count descriptors, scalar values that

describe several atoms, bonds, or functional groups in the molecule, e.g., molecu-
lar weight.
• 1D Descriptors: These descriptors capture molecular properties in one dimension
along a linear sequence or chain of atoms, e.g., structural fragments or fingerprints.
• 2D Descriptors: These descriptors provide information about the structure on a molec-
ular level and its properties within a 2D plane, e.g., topological polar surface area
(TPSA) and graph invariants.
• 3D Descriptors: These descriptors describe the molecular properties in 3D space, con-
sidering the spatial arrangement of atoms, e.g., autocorrelation descriptors, substituent
constants, surface:volume descriptors, quantum, chemical descriptors, 3D-MoRSE de-
scriptors, WHIM descriptors, GETAWAY descriptors, size, steric, surface, and volume
descriptors.
• 4D Descriptors: These descriptors encompass properties that change over time or
involve spatiotemporal aspects, e.g., drug dissolution rate, Volsurf, and GRID or
CoMFA methods.

Table 1. The most common 0D to 4D chemical descriptors for QSAR/QSPR analysis.

Descriptor
Descriptor Type Example
Dimension
The molecule’s atoms, bonds, and
0D Molecular weight, LogP (partition coefficient)
functional groups count
1D Molecular properties in a linear manner Molecular Formula, SMILES & SELFIES
Molecular fingerprint (e.g., Morgan fingerprint),
2D Topological polar surface area (TPSA)
Constitutional descriptors (e.g., atoms, bonds, and rings count)
Molecular shape descriptors (e.g., volume, surface area),
3D Special properties of a molecule
Pharmacophore features
Molecular dynamics descriptors, solvent accessible surface area
Electrostatic potential descriptors with (SASA), radius of gyration (Rg), Time-dependent properties (e.g.,
4D
spatiotemporal aspects dynamic polar surface area (dPSA), time-dependent
dipole moment

These molecular descriptors have been used to select the most relevant properties.
MoDeSus is an ML-based tool used to determine the most informative molecular descriptors
for QSAR studies. Molecular descriptors allow for ligand-based scaffold hopping for hit
and lead optimization, which speeds up the early stages of drug development and has been
used to compare QSAR and QSPR models. Although each type of descriptor plays a vital
role, 3D and 4D descriptors have shown the most significant contribution to identifying
Int. J. Mol. Sci. 2023, 24, 11488 5 of 15

active molecules and potential drug targets. Furthermore, 4D descriptors like CoMFA and
GRID have been used to identify active sites of receptors and characterize interactions
providing insight into the functional properties of small molecules [41–43].

4. QSAR
Based on its physicochemical characteristics, a ligand’s biological response or activ-
ity can be predicted using QSAR analysis [38]. QSAR modeling techniques have been
used to find prospective drug candidates, and these have developed into AI-based QSAR
methods [44]. Modern machine learning approaches can be applied to model QSAR
or quantitative structure–property relationships (QSPR) and create predicative models
based on artificial intelligence [45,46]. Chemoinformatics, QSAR, and machine learning
applications have been used to showcase different structure-based, ligand-based, and
machine-learning-based approaches for drug development. QSAR/QSPR models employ
information on multiple levels, e.g., chemical data, descriptors, molecular graphs, finger-
prints, similarity analyses, and molecular dynamic simulations, to predict the most optimal
properties of a potential drug.
Structure–activity relationship (SAR) analysis investigates how the chemical structure
of a compound relates to its biological activity or properties and plays a crucial role in
exploring potential effects of bioactivity on changes in the chemical structure of drugs.
Quantifying the degree of the structural or chemical similarity between molecules and
extrapolating chemical attributes from molecular similarity are the goals of similarity
analysis [47]. Similarity search mainly aims to identify compounds with similar bioactivity
to a reference molecule but with different chemotypes. This results in scaffold-hopping
derivatives acquired from a reference compound with a novel core structure. Fragment
replacement approaches, fingerprint-based similarity search, pharmacophore matching,
and 3D shape-based similarity search are all examples of computational research for scaffold
hops. Designing molecules of novel scaffolds with increased pharmacological activity and
identical 3D structure but a multimodal deep transformer neural technique for scaffold
hopping aids the distinct 2D structure [48–51].
SARs are also employed in clustering, inter-molecular comparisons, outlier and nov-
elty analysis, diversity quantification, and outlier analysis. Molecular datasets are used
by AIMSim, a unified platform, to carry out similarity-based tasks using binary similarity
metrics and molecular fingerprints [52]. In a study, a tool called the similarity ensemble
approach (SEA) was used to estimate the accuracy of k-nearest neighbors (kNN) QSAR
models constructed for known ligands of each GPCR target individually to discover ac-
tive and inactive molecules [53]. ChemSAR, another tool, offers an integrated web-based
platform for creating SAR classification models, and it is also an online pipelining plat-
form for molecular SAR modeling. For the identification and structural organization of
analog series, SAR analysis, and compound design, various researchers have employed
the SAR Matrix (SARM) concept [54–56]. DeepSARM, which combined deep learning and
generative modeling, was introduced, expanding the scope of the SARM technique. This
improvement made it possible to create target-based analogs by considering the chemical
information from related targets to increase structural uniqueness and variety [57].
The current approach to constructing QSAR models typically involves generating
descriptors for the compounds in the training set, applying descriptor selection algorithms,
and employing statistical fitting methods to build the model. Nevertheless, there have been
investigations into the potential for developing high-quality, interpretable QSAR models
for large and diverse datasets without relying on pre-calculated descriptors. To achieve this
objective, these studies explore using deep learning techniques, specifically long short-term
memory neural networks [58].

4.1. QSAR Modeling

The standardized procedure for building QSAR models in drug discovery encom-
passes a series of modular steps that incorporate the afore-discussed chemoinformatics and
Int. J. Mol. Sci. 2023, 24, 11488 6 of 15

machine learning techniques. By following the protocol, QSAR modeling aided by ML and
DL (deep learning) can predict the properties or activities of chemical compounds, toxicity,
and other related physiochemical properties.

4.2. Molecular Encoding

Molecular encoding is like chemical data representation transformation, as discussed
before. Compounds’ chemical characteristics and attributes are directly deduced from
their chemical structures or by looking up experimental findings. This process involves
extracting relevant information from the molecular structure, such as atom types, bond
types, functional groups, and physicochemical properties.

4.3. Feature Selection

Feature selection in QSAR aims to identify the most informative and relevant features
from a larger set. It involves techniques such as univariate analysis, filter methods, wrapper
methods, and embedded methods. To determine the most pertinent attributes and lessen
the dimensionality and collinearity of the feature vector, hybrid feature selection, feature
learning methodologies, and unsupervised learning techniques are applied. These tech-
niques have successfully preserved a fair computing effort without reducing the precision
of the final QSAR models [59].

4.4. Model Training

During the model training and learning phase of QSAR modeling, a supervised
machine learning model is generally employed to uncover an empirical function that
effectively maps input feature vectors to biological responses. This function is optimized
to achieve the best possible mapping. It is crucial to carefully select and consider the SAR
datasets and descriptors used for training and model validation to ensure the development
of accurate QSAR models [60].

5. Machine-Learning-Based QSAR Modeling

Unsupervised learning and supervised learning are two categories of machine
learning models. In supervised learning, a model is trained with labeled data to produce
predictions based on known input–output correlations (for example, support vector
machines and linear regression). Unsupervised learning analyzes unlabeled data to
discover underlying patterns and relationships without explicit guidance (e.g., clustering
and dimensionality reduction).
QSAR involves training supervised learning models using labeled datasets, where
the input features represent the chemical structures and the output labels represent the
corresponding biological activities, toxicity, or other properties. Furthermore, unsupervised
learning techniques can be applied in QSAR to uncover hidden patterns or relationships
within the chemical data, such as clustering similar compounds based on their structural
similarities or reducing the dimensionality of the dataset. QSAR models can be built using
traditional methods like random forest, multiple linear regression, Naïve Bayes, k-nearest
neighbors, support vector machine, or deep neural network (DNN).
The hit-to-lead optimization and hit-to-hit identification can be performed using ML-
based QSAR models. The automated hit identification and optimization tool (A-HIOT),
among other sophisticated virtual screening frameworks, can be employed to find and
improve hits for fixed protein receptors. A-HIOT uses numerous open-source methods to
combine chemical and protein space and produce high-quality predictions [61]. To show
that deep neural networks (DNN) and random forests (RF) were superior in hit prediction
efficiency, comparison studies between DNN and other ligand-based virtual screening
(LBVS) approaches were conducted. A scan of an in-house library of 165,000 chemicals
revealed numerous triple-negative breast cancer (TNBC) inhibitors as powerful hits using
DNN. From a small-size training set of 63 compounds, a potent mu-opioid receptor (MOR)
Int. J. Mol. Sci. 2023, 24, 11488 7 of 15

GPCR proteins agonist was found. One hundred seventy-six possible antimalarial hits
were found by integrating QSAR and virtual screening [62,63].

5.1. Regression Analysis

Regression analysis is a statistical technique for simulating the relationship between
a dependent variable and one or more independent variables. It seeks to identify the
line with the best fit that minimizes the sum of the squared residuals. The relationship
between variables can be inferred by estimating the regression equation coefficients. Early
QSAR techniques like Hansch and Free Wilson analysis heavily utilized multivariate linear
regression. Since QSAR deals with multidimensional data, the twin curses must be tackled
before further processing chemical data. Many variations and ensembles of regression
analysis are now employed for predictive modeling in QSAR.
By fusing aspects of network analysis and piecewise linear regression, interpretable
QSAR models have been created using network-based linear regression. In a study on
inhibitors of polo-like kinase-1 and linear regression, to find prediction models of an ex-
tensive and structurally varied dataset of 530 chemicals, QSAR models were created. A
discriminant–regression model (DIREM), a common discrete–continuous QSAR technique,
is another form of regression model that combines discriminant and regression studies to
investigate structure–activity connections for substances. The effectiveness of PLS-based
QSAR models was assessed, and they were compared with the outcomes of multiple linear
regression (MLR) and principal component regression (PCR) in a comparative analysis
study on 5-nitrofuran-2-yl derivatives as inhibitors of Mycobacterium TB H37Rv. Com-
pared to PCR, the findings of the PLS and MLR analyses demonstrated significantly higher
predictive power and reliability, attesting to the dependability of these techniques [64–68].
Although numerous medication optimization studies have successfully used linear regres-
sion analysis and its derivates, there are still substantial drawbacks, including underlying
linearity, overfitting, restricted interpretability, the necessity of high-quality data, and false
vector space assumptions.

5.2. K-Nearest Neighbor

The k-nearest neighbors (kNN) algorithm represents labeled and unlabeled data nodes
in a multidimensional feature space. The k-nearest neighbors (kNN) methodology is a
straightforward distance-learning strategy in which an unknown member is categorized
based on most of its k-nearest neighbors. Using a majority-voting rule, it assigns labels to
query points by transferring them from the nearest neighbors. This approach leverages the
proximity of data points in the feature space to make predictions [69].
Choosing the right number of nearest neighbors to utilize in the kNN algorithm can
be challenging because doing so can lead to unfavorable false-positive or false-negative
rates. This was addressed by introducing the similarity ensemble approach (SEA), which
proved to be a more organized method for determining the right number of neighbors in
kNN analysis. The SEA compares chemical similarity values to a randomized background
score, similar to the BLAST sequence similarity search method [70].
A study developed a 3D QSAR model for 30 drugs with anti-HIV activity using a
kNN model. According to most of the training set’s nearest neighbors, this kNN model
categorized the chemicals. The technique determined the essential structural characteristics
that lead to the compounds’ anti-HIV efficacy [69]. Another study developed QSAR models
for 50 compounds with an anti-HIV activity using the kNN–molecular field analysis
method. The results showed the importance of electrostatic and steric interactions in
influencing the anti-HIV activity of the compounds [71]. Consensus kNN QSAR was used
in a study and proved to be a practical method for quickly screening the estrogenic activity
of organic compounds. It is a flexible method for predicting the estrogenic activity of
organic compounds in silico [72]. Utilizing a deep neural network in conjunction with the
kNN approach to creating QSAR models for a collection of 1000 chemicals having anti-
cancer activity was also claimed to be helpful. According to the study, the main structural
Int. J. Mol. Sci. 2023, 24, 11488 8 of 15

characteristics contributing to the compounds’ anti-cancer efficacy could be determined

using the kNN approach [73].

5.3. Naïve Bayes

Naïve Bayes is a probabilistic classifier commonly assuming that features are inde-
pendent, simplifying the modeling process. It determines the probability of correct label
assignment by considering the prior probability distribution of labels in the training set. It
assumes conditional independence between multiple labels and calculates probabilities for
each label individually. The PASS program, a notable example, utilizes this approach for
predicting drug activities [74].
On 18 sizable, varied in-house QSAR datasets, a study examined the capacity of
Pipeline Pilot Naïve Bayes (PLPNB) and random forest to produce precise predictions.
According to the study, PLPNB could predict binary and multicategory activities with
accuracy and was computationally efficient. Large-scale virtual screening for important
pharmacological features, such as cytochrome P450 inhibition, human plasma protein
binding, and animal model bioavailability, have demonstrated their effectiveness [75,76].
Another study showed that when used in QSAR modeling, the Naïve Bayes model delivers
the lowest mean error when the data points are distributed uniformly. This study uses
QSAR as an example to demonstrate the Naïve Bayes model’s optimality [77]. In a com-
parative study to choose the best learning algorithm and optimal feature selection, Naïve
Bayes was shown to be one of the best-performing algorithms for small datasets [78].

5.4. Support Vector Machine

Support vector machines (SVM) are widely used in QSAR due to their ability to han-
dle high-dimensional data and nonlinear relationships. They construct a hyperplane that
maximally separates different classes in the feature space. SVMs have demonstrated excel-
lent performance in various QSAR applications, such as predicting compound activities,
toxicity, and bioavailability. Their versatility and robustness make them valuable tools in
QSAR modeling. A framework known as “ML-QSAR” was established in a study in which
machine learning methods were used for QSAR modeling. SVM was discovered to be one
of the most often used machine learning algorithms in QSAR modeling. The framework
was created to facilitate the selection of appropriate strategies among existing algorithms
according to the application area requirements and to help develop and improve current
approaches [79].
A study developed multiple QSAR methods using several ML algorithms, including
SVM, to predict the activity of active substances against Pseudomonas aeruginosa. The
study found that SVM could better predict the compounds’ activity accurately compared to
other models [80]. Another study examined SVM’s effectiveness and prognostication power
in HEPT derivative QSAR modeling. This investigation showed that SVM outperformed
different approaches, including artificial neural networks, in terms of prediction [81]. SVM
was also used to simulate phenethylamines’ structure–activity relationships (SAR). To
categorize antagonists and agonists and forecast their effects, the study used SVM, which it
discovered to be a reliable method in the SAR/QSAR field [82].
Another study evaluated the effectiveness of 16 machine learning algorithms, includ-
ing SVM, on 14 QSAR datasets and concluded that various ML algorithms offered different
QSAR modeling approaches to uncover the connections between compound structures and
properties [83]. When used for large-scale ligand-based predictive modeling, SVM predicts
the properties of new, unknown compounds and can achieve good predictive performance
for large-scale QSAR modeling [84]. SVMs have also been applied in a QSAR investi-
gation involving ethyl 2-[(3-methyl-2,5-dioxo(3-pyrrolidinyl)) amino]-4-(trifluoromethyl)
pyrimidine-5-carboxylate derivatives, targeting the transcription factors activator protein
(AP)-1 and nuclear factor (NF)-kB [85]. To determine the structural elements that give
aminopyrimidine-5-carbaldehyde oxime derivatives a potent vascular endothelial growth
factor (VEGF)-2 inhibitory action, a genetic variable selection approach was combined with
Int. J. Mol. Sci. 2023, 24, 11488 9 of 15

SVMs. This integrated approach successfully identified several critical structural features
associated with the desired biological activity, proving SVM helpful in QSAR modeling [86].

5.5. Convolutional Neural Networks, Recurrent Neural Networks, Deep Neural Networks, and
Ensemble Methods
By leveraging the power of neural networks with multiple hidden layers, deep learning
models can effectively learn complex relationships between molecular structures and their
related biological activities. In QSAR, deep learning models, such as convolutional neural
networks (CNNs), recurrent neural networks (RNNs), and deep neural networks (DNNs),
have been utilized to analyze and predict various properties of molecules, including binding
affinity, activity, toxicity, and bioavailability. These models and their ensemble methods
have been applied in QSAR studies to enhance models’ accuracy and predictive power.
CNNs have successfully captured molecular features and patterns from 2D chemical
structures and search spaces. RNNs have been utilized to model sequential data, such as
molecular fingerprints and SMILES strings. DNNs have effectively learned complex rela-
tionships between 3D and 4D molecular descriptors and their respective bioactivity data.
Ensemble methods combining CNN, RNN, and DNN have been employed to improve
prediction performance. These advanced neural network topologies and ensemble methods
have been extensively used in modeling QSAR/QSPR features of small compounds and
conducting pharmacokinetic and pharmacodynamic studies, alongside work in other fields
of chemoinformatics. In particular, CNN’s unmatched capacity for image analysis made
it possible to visualize protein structures as ‘3D images’ with four separate atom-type
channels. These 3D-CNNs were used to compare the microenvironments of amino acids
and predict how mutations might affect the structure of proteins [87]. A Transformer–CNN
architecture was suggested in a study for QSAR modeling and interpretation. Convolu-
tional and element-wise feed-forward layers were used in place of all recurrent units in
the design, and it was discovered that the Transformer-CNN architecture produced good
results for small datasets and converged quickly for QSAR tasks [88].
Recurrent neural networks (RNNs), also known as long short-term memory (LSTM)
networks, are built to recognize both short-term and long-term dependencies in sequential
input. For applications like de novo drug design, where they learn the structural patterns
and rules from SMILES strings to produce novel molecules, LSTM networks have been
used in the context of QSAR. Deep reinforcement learning, variational autoencoders, and
generative adversarial networks (GANs) are other cutting-edge methods used to gener-
ate compounds with precise molecular features while learning latent representations of
molecules. These methods aid in the discovery of novel medication candidates and the
exploration of new chemical territory [27,89–93]. A study that proposed an ensembled
RNN–CNN architecture, DeepCpG, for DNA methylation analysis concluded that com-
bining RNN and CNN improved the performance of the QSAR model [94]. To perform
QSAR analysis utilizing three-dimensional photographs of chemical structures, a brand-
new DL-based method dubbed DeepSnap was created. Without extracting descriptors, this
method may also forecast the potential toxicity of many compounds to different receptors.
To perform QSAR analysis utilizing three-dimensional photographs of chemical structures,
a brand-new DL-based method dubbed DeepSnap was created. Without extracting descrip-
tors, this method may also forecast the potential toxicity of many compounds to different
receptors [95]. CNN, RNN, and deep-learning-based methods have also shown promising
results in QSAR modeling.

6. Validation of ML-QSAR Models

ML-QSAR models are typically assessed using established metrics like sensitivity,
specificity, precision, and recall. In cases where the dataset is unbalanced, the area un-
der the curve (AUC) obtained from receiver operating characteristic (ROC) curves can
be employed. QSAR models can also be evaluated by various methods, such as external
validation, conformal prediction methods, and evaluation of QSAR equations for virtual
Int. J. Mol. Sci. 2023, 24, 11488 10 of 15

screening. External validation is the primary method for evaluating the accuracy of gener-
ated models for the activity prediction of compounds that have not yet been synthesized.
Understanding the variables that control molecular characteristics and creating new com-
pounds with advantageous features depend on QSAR models, which provide information
on the association between activities and structure-based molecular descriptors [96,97].
Even though 3D-QSAR techniques like CoMFA take structural conformation into ac-
count, they are computationally intensive and can introduce errors related to conformation
prediction, ligand orientation, and structural alignment. Consequently, 2D-QSAR models
can provide a viable alternative and sometimes even outperform 3D-QSAR strategies [38].
The creation of verified models for accurate and precise prediction of a compound’s biologi-
cal actions is the ultimate goal of QSAR analysis. When creating QSAR models, metrics like
R2 and QCV2 are generally optimized. The performances of the final models are assessed
using comparable metrics computed on external datasets [98].
A comparative study on 5-nitrofuran-2-yl derivatives as inhibitors of Mycobacterium
tuberculosis H37Rv used statistical parameters, including squared correlation coefficients,
cross-validated correlation coefficients, and Fischer’s value for statistical importance, to
assess the quality of the generated QSAR models. Another study examined several statisti-
cal parameters of 44 published QSAR models for biologically active substances that were
externally validated and presented in academic journals. They concluded that using the
coefficient of determination (R2) alone was insufficient to determine if a QSAR model was
viable. There are benefits and drawbacks to these defined criteria for external validation
that should be considered in QSAR investigations [99].

7. Interpretability and Explainability of ML-QSAR Models

The creation of verified models for accurate and precise prediction of a compound’s
biological actions is the ultimate goal of QSAR analysis. The interpretability and explain-
ability of ML-QSAR models promote transparency, reproducibility, and trust in the models’
predictions, allowing researchers and stakeholders to make informed decisions regarding
drug discovery and development. Six artificial datasets of varying degrees of complexity
were produced as part of a study to compare various QSAR model interpretation tech-
niques. These datasets were used in the study’s investigation of a wide range of descriptor
and algorithm pairings and the Structure–Property Correlation Index (SPCI) method of uni-
versal interpretation. The study showed that predictivity might decline more quickly than
interpretation performance and that even models with good predictivity may occasionally
have subpar interpretation performance [100].
Various techniques can enhance the explainability and interpretability of ML-QSAR
models. Feature importance analysis can identify the most influential molecular descrip-
tors or features contributing to the model’s predictions. Visualization methods, such as
heat maps or feature importance plots, can aid in understanding the relationships be-
tween features and the predicted outcomes. Additionally, model-agnostic techniques like
LIME (Local Interpretable Model-Agnostic Explanations) [101] or SHAP (Shapley Additive
Explanations) [102] can provide insights into individual predictions by highlighting the
contributions of each feature. A new way to visualize QSAR models is described in a publi-
cation that streamlines analysis by adding a new measure of model similarity. The method
relies on projecting models into a two-dimensional plane, where the separation between
two models is proportional to the variation in their expected activities [103]. Another study
creates predicted QSAR models that may be projected onto the atoms of a molecule by
combining direct kernel-based PLS with Canvas 2D fingerprints. The work offers a model
visualization that can be used to determine which atoms are most important for forecasting
activity [104].
Being unable to explain why a neural network generates a prediction is a significant
impediment to the application of AI models due to the ‘black box’ approach. In addition
to discouraging chemists from utilizing deep learning predictions, this has caused neural
networks to pick up undetectable bogus correlations. Counterfactual interpretation is a
Int. J. Mol. Sci. 2023, 24, 11488 11 of 15

technique for reading ML models that can be used to comprehend why a model generates
a specific prediction. Counterfactuals are local interpretations that can disclose the contri-
butions of atoms or fragments within particular molecules to identify the most beneficial
or detrimental motifs to consider for future alterations in the context of QSAR models.
Because they resemble counterfactuals, instance-based techniques have been claimed to
provide ‘natural’ model interpretations for researchers. Various approaches to interpre-
tation have been established; however, there are no appropriate standards to assess how
well they apply to the interpretation of QSAR models. An approach known as STONED
(Structure–Topology Optimization for Novel Explanatory Discoveries) is suggested in a
study; it produces molecular counterfactuals for any model. These molecular counterfac-
tuals offer skeletal, molecular structure-based explanations. All molecules produced by
STONED are legitimate substances, so the method does not require training a counterfac-
tual generator. This simplifies the procedure and eliminates the necessity of a generative
counterfactual creator [100,105,106].

8. Conclusions
Applying machine learning techniques in chemoinformatics has contributed signif-
icantly to discovering and designing highly effective drugs. This paper highlights the
significant role of chemoinformatics and ML-based QSAR in drug discovery and develop-
ment. Integrating computational approaches with large-scale data analysis has revolution-
ized the field, enabling efficient exploration of chemical space and predicting biological
activities. Multiple algorithms built for QSAR modeling significantly highlight features
necessary for further designing small molecules. They have demonstrated their effective-
ness in predicting molecular properties and activities, aiding in compound prioritization
and optimization.
The future of chemoinformatics and QSAR modeling holds promising opportunities
for further advancements. Integrating QSAR models with molecular docking techniques
can enhance the accuracy of binding affinity predictions and provide valuable insights into
the interaction between ligands and target proteins. Fragment-based design approaches
can benefit from QSAR models by guiding the selection and optimization of fragments to
develop novel drug candidates. Additionally, integrating QSAR models with de novo drug
generation methods, such as deep learning and generative modeling, opens up possibilities
for computer-assisted design and discovering new molecules with desired properties.
This convergence of QSAR models with molecular docking, fragment-based design,
and de novo drug generation methods holds great potential to accelerate the drug discovery
process, reduce costs, and increase the success rates of identifying novel therapeutic agents.
Continued research and development in this area will undoubtedly pave the way for more
efficient and precise drug design strategies, ultimately benefiting patients and advancing
the field of pharmaceutical sciences.

Funding: This research received no external funding.

Conflicts of Interest: The authors declare no conflict of interest.

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