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Combinatorial Chemistry & High Throughput Screening, 2022, 25, 1818-1837

REVIEW ARTICLE
ISSN: 1386-2073
eISSN: 1875-5402

COMBINATORIAL CHEMISTRY &

HIGH THROUGHPUT SCREENING
Accelerated Technologies for Biotechnology, Bioassays,
Medicinal Chemistry and Natural Products Research

Artificial Intelligence (AI) in Drugs and Pharmaceuticals

Impact
Factor:
1.714

BENTHAM
SCIENCE

Adarsh Sahu1*, Jyotika Mishra1 and Namrata Kushwaha2

Combinatorial Chemistry & High Throughput Screening

1
Department of Pharmaceutical Sciences, Dr. Harisingh Gour Vishwavidyalaya, Sagar, MP, India; 2Sri Aurobindo In-
stitute of Pharmacy, Indore, MP, India

ARTICLE HISTORY
Received: August 02, 2021
Revised: October 11, 2021
Accepted: October 19, 2021
DOI:
10.2174/1386207325666211207153943
Abstract: The advancement of computing and technology has invaded all the dimensions of sci-
ence. Artificial intelligence (AI) is one core branch of Computer Science, which has percolated to
all the arenas of science and technology, from core engineering to medicines. Thus, AI has found
its way for application in the field of medicinal chemistry and heath care. The conventional meth-
ods of drug design have been replaced by computer-aided designs of drugs in recent times. AI is
being used extensively to improve the design techniques and required time of the drugs. Addition-
ally, the target proteins can be conveniently identified using AI, which enhances the success rate of
the designed drug. The AI technology is used in each step of the drug designing procedure, which
decreases the health hazards related to preclinical trials and also reduces the cost substantially. The
AI is an effective tool for data mining based on the huge pharmacological data and machine learn-
ing process. Hence, AI has been used in de novo drug design, activity scoring, virtual screening
and in silico evaluation in the properties (absorption, distribution, metabolism, excretion and tox-
icity) of a drug molecule. Various pharmaceutical companies have teamed up with AI companies
for faster progress in the field of drug development, along with the healthcare system. The review
covers various aspects of AI (Machine learning, Deep learning, Artificial neural networks) in drug
design. It also provides a brief overview of the recent progress by the pharmaceutical companies in
drug discovery by associating with different AI companies.

Keywords: Deep learning, machine learning, artificial neural network, drug design, drug discovery, pharmaceuticals.

1. INTRODUCTION where the ligands are grown methodically to interact electro-

The process of drug discovery is complex, expensive and
strenuous as a single molecule has to be identified from a
range of 1060 -10100 probable molecules. The selected mole-
cule should comply with characteristics like drug metabo-
lism and pharmacokinetic profile (DMPK), bioactivity and
feasible synthetic methods. The period required from the
recognition of the drug to its implementation is around 3 - 5
years. Apart from the period, numerous compounds (100 -
1000) have to be synthesized and used for clinical trials [1].
The designed drugs should also find their target appropriate-
ly by moving through the body, which is another challenge
during the design of a particular drug. Additionally, the
pharmacogenetic factors like a response to a drug based on
genetic variation and toxicity of chemicals propelled due to
interaction of the drug with undesired proteins, are other
hindrances faced during the process of drug design.
The labour, challenges and time have been potentially ebbed
by the development of de novo algorithms to design the spe-
cific drug. The approaches used initially were structure-based,
*Address correspondence to this author at the Department of Pharmaceuti-
cal Sciences, Dr. Harisingh Gour Vishwavidyalaya, Sagar, MP, India;
E-mail: adarshniper@gmail.com
statically and sterically with the target site. However, the
compounds designed by this process exhibited limitations
like weak properties of DMPK [2]. Another approach fol-
lowed for de novo design is making a virtual library of the
possible drug structure followed by exploring the practical
feasibility through docking studies [3]. Nevertheless, the
reaction conversion is predefined, which confines these
methods within a certain sphere.
Artificial intelligence (AI) is a recent and promising ap-
proach for drug discovery and design processes. Machine
learning is a part of AI which has been used extensively in
the arena of pharmaceutical science. Scientists and research-
ers have become more competent and skilled due to the
availability and storing of data in machines. The progress
and application of machine learning have led to the estab-
lishment of fundamental algorithms and their application.
The science of devising intelligent machines was termed
artificial intelligence by John McCarthy at a Dartmouth Con-
ference in 1956 [4]. AI encompasses a multitude of disci-
plines like mathematics, linguistics, computer science, psy-
chology, neuroscience and others. The application of AI is
diverse with basic methods like a representation of
knowledge, quest for a solution, maintenance and acquire-
ment of knowledge, logical reasoning, along with machine

1875-5402/22 $65.00+.00 © 2022 Bentham Science Publishers

Artificial Intelligence (AI) in Drugs and Pharmaceuticals
learning. This review encompasses the application of AI in
drug discovery during the last 5 years.
1.1. Initiation of Artificial Intelligence in Pharmaceuti-
cals
Artificial intelligence was initially introduced in the
realm of molecular biology and chemistry for predicting the
sequencing of the secondary protein structure [5]. The con-
cept of the application of AI in the arena of drug research
was carried out for understanding the structure-activity rela-
tionship based on Hammett’s equation describing a relation-
ship between the equilibrium constants and reaction rates for
derivatives of benzene [6]. This was followed by the study
for the recognition and optimisation of the different bioactive
molecules by Hansch who was the father of QSAR [7]. The
chemical consequences on the biological process were ana-
lysed through a large number of AI techniques by different
medicinal chemists [8]. The similar patterns shared among
various chemical structures were analysed and used as bases
for studying the in vitro biochemical effects and analogous
physicochemical properties [9] by a route termed as pattern
recognition method [10]. Again, the neural networks were
used in the pharmaceutical industry as they had the capabil-
ity for the identification of patterns and could be used as
engines [11]. The initial proper application of the neural
networks was used for forecasting the mechanism of action
of a cancer drug [12]. The complete molecular design meth-
ods based on machine learning and AI possessed the efficacy
of solving the problems, adjusting with the novel situations
and learning from experiences [13]. Thus algorithms related
to machine learning like random forest (RF) [14], and sup-
port vector machine (SVM) [15] were put forth. These pro-
grammes were used for the identification of all the signifi-
cant features of the molecules for a precise prediction. The
method of deep learning was developed for studying the
multifaceted association between the parameters like toxici-
ty, bioactivity and molecular structures [16]. The difficulties
of prediction for the toxicity of the drugs (NIH Tox21) [17]
and forecasting of the activities of the compounds (Kaggle
challenge) [18] were overcome by the application of the deep
learning methods. The other commonly used deep learning
modelling methods are variational autoencoder (VAE), [19]
recurrent neural network (RNN) [20] and generative adver-
sary network (GAN) [21].
1.2. Quest for Novel Drugs Using AI
The term ‘chemical space’ is an important parameter for
the execution of AI in the field of drug discovery. An exclu-
sive and superior quality molecule can be computationally
identified using chemical space from an assembly of numer-
ous feasible molecules [22]. Thus the number of compounds
to be synthesised is narrowed down by the application of AI
technology which boosts the economy in the arena of phar-
maceutical research. A well-known protein related to a par-
ticular disease is selected and the AI technology is imple-
mented for designing a drug that can interact appropriately
with the target protein for eliminating the symptoms of the
disease. There are software programmes for harmonizing the
biochemical properties and biophysical structures of around
150,000 proteins with a huge number of molecules for ex-
posing the exact molecule which would interact with the
Combinatorial Chemistry & High Throughput Screening, 2022, Vol. 25, No. 11 1819
exact protein. Apart from the identification of the adequate
drug molecule, there are still other hurdles to overcome, like
the drug should endure the metabolic process of the liver and
possess excellent transport capability to reach the target site
from the gut through the bloodstream. Other factors to be
considered during the drug design are that the molecule
should be effectively eliminated from the body prior to its
potential of being toxic and should circumvent any interac-
tion with other proteins which may create health issues. De-
spite accounting for all these factors, there remains a major
pertaining challenge. The identification of a particular mole-
cule interacting with a specific protein owes the potential to
interact with around 300 other similar proteins. Additionally,
around 100 different proteins are responsible for complicated
diseases like Alzheimer’s and cancer. Thus targeting a spe-
cific protein using a specific drug molecule is not the proper
solution for these maladies.
Thus, the development of AI is used for the complex
identification of drugs which can relate with around 20 dif-
ferent proteins, while evading hundreds of other similar pro-
teins. The genetic data of a multitude of individuals are gath-
ered for recognition of the difference in the proteins. The AI
software would analyse the data and specify a particular drug
for the patient depending on the symptoms.
The identification of the target molecule is the initial attempt
of drug discovery. This information is gathered by AI from the
sample of human tissues, fluids and blood according to Berg’s
approach. Thus the AI assembles data from diverging fields like
metabolomics, genomics, lipidomics, proteomics and other re-
lated physiological factors. The samples were collected from
both healthy individuals and other individuals suffering from
the disease and the live cells were exposed to various pathologi-
cal conditions in the laboratory. The processes like the rigidity
of the membrane or the capability of the cell to generate energy
produce different data which are processed by deep-learning
software. The software analyses the data and recognises the
protein responsible for the specific disease. Additionally, the
software could identify the genes responsible for the malady
which is also termed as an approach called precision –medicine
approach. The patients could be examined about the efficacy of
the drug, before its ingestion.
1.3. Impact of AI in Decreasing the Cost n Drug Design
The pharmaceutical companies decide the final cost of
the drugs, based on the market analysis [23]. AI can be ap-
plied for determining the market price through the analysis
of different factors, controlling the drug cost after its produc-
tion [24]. The factors influencing the cost of a manufactured
drug are market share value of the drug, cost regulatory
schemes of the country, total budget for the manufacturing of
the drug, cost of the reference product available in the mar-
ket, and the policies for determining the price by the brands
[25]. These factors are analysed using ML for forecasting the
final cost of the drug. Conventional drug discovery ap-
proaches require synthesizing a hundred derivatives and then
analysing their medicinal properties which were very time
consuming and cost a lot of money. But now using AI we
can screen compound and can select the best compounds
which will save money and lots of efforts [15, 16, 18]. An-
other AI technique is the In competitor, which is a competi-
1820 Combinatorial Chemistry & High Throughput Screening, 2022, Vol. 25, No. 11
Table 1. Different AI models used in drug discovery.
Process of Drug Discovery Designing of Drugs
Analysis of PPI
Identification and study of targets
Analysis of protein folding
Drug repurposing
Discovering a hit Activity scoring
Virtual screening
De novo drug design
From hit to lead
QSAR
Analysis of absorption, distribution, metabolism, excre-
Optimisation of the lead molecule
tion and toxicity
tive platform for estimating the data related to market prices
by different brands [26].
2. AI AND DRUG DESIGN
The structure-based drug discovery mainly emphasises
the 3D structure of the target protein [27]. The 3D environ-
ment of the binding site of the ligand is significant during the
design of the target protein. The de novo design of protein
and homology modelling is the conventional method [28]
which has been replaced by sophisticated AI technologies.
Among the different tools, AlphaFold demonstrated high
efficacy in the accurate prediction of the 3D structure of
drugs that targeted a specific protein based on primary se-
quences of the proteins. This tool depends on the DNN,
which mainly forecasts the protein properties like the angles
between the neighbouring peptide bonds and the distances
between the amino acid pairs by studying the primary se-
quence. The analysis of the 3D structure is carried out by
combining both the probabilities into score functions which
are used to investigate the target protein structure and finally
predict the drug molecule.
The interaction between the protein and drug is analysed
using either quantum mechanics or hybrid methods of both
quantum mechanics and molecular mechanics [29]. The
quantum effects are conceded at the atomic level, thereby
enhancing the accuracy of the process. However, the time
required for the methods based on quantum mechanics is
more as compared to the molecular mechanics method [30].
The intrusion of AI methods in the analysis of quantum me-
chanics decreased the time and cost [31]. The analysis and
atomic simulations of the electrical properties of the mole-
cule can also be done by AI. Moreover, the potential ener-
gies of the small molecules are analysed using deep learning
methods thus substituting the analysis of quantum chemistry
by machine learning. The different AI models for drug dis-
covery are shown in Table 1 [32-38].
2.1. De Novo Design Process
The technique of designing new drug molecules devoid
of reference compounds is termed as de novo design process,
which has been conducted using different software [39].
Sahu et al.
AI Models Refs.
FD/DCA [32]
CNN [33]
Network pathology [34]
SVM. RF, 3D graph CNN [33]
SVM, AAE [35]
Deep learning, VAE, AAE [36]
Machine learning methods, DNN [37]
CNN, neural network [38]
2.1.1. Recursive Neural Network
The de novo process has successfully used the recursive
neural networks (RNN), which operate through the inputs of
sequential information [40-43]. The RNN produces the
chemical structures by the application of SMILES strings to
decode the chemical structures in form of letters. The RNN
is fed with chemical structures from existing databases like
ChEMBL for familiarising the software with the grammar of
the SMILES strings. Thus RNN was used for generating a
multitude of SMILES strings [40] and new peptide structures
[41]. The required properties were incorporated by the rein-
forcement learning process.
2.1.2. Transfer Learning Process
The drugs with expected chemical structures were de-
signed using the transfer learning process. The network is
fed with the SMILES grammar consisting of an extensive
training set primarily followed by training the molecules
having the required activities. Thus the desired drug can be
screened for a particular chemical space [20]. In a study, five
molecules were prepared using this method and four mole-
cules among these were found to be active against the recep-
tors of nuclear hormones [38]. However, the size of the
chemical space is yet to be explored.
2.1.3. Autoencoder
One artificial intelligence approach is autoencoder which
is of two types: adversarial autoencoder and variational auto-
encoder (Figs. 1 and 2).
The variational autoencoder comprises double neural
networks: a decoder network and an encoder network. The
chemical structures represented by SMILES are transformed
into a continuous vector of a real value corresponding to
latent space by the encoder network. The vectors from the
latent space are transformed into chemical structures by the
decoder. In silico model was used for the identification of
the accurate solutions in the latent space, which was used for
back converting the vectors into the real molecules using the
decoder network. A single molecule supersedes the back
translations with minor modifications in the structure. A
favourable route for the molecules with good target charac-
teristics was obtained by the application of the latent space
Artificial Intelligence (AI) in Drugs and Pharmaceuticals Combinatorial Chemistry & High Throughput Screening, 2022, Vol. 25, No. 11 1821

  
































 























 

































 


























Fig. (1). Variational autoencoder, a type of autoencoder [45]. (A higher resolution / colour version of this figure is available in the electronic
copy of the article).

  
































 























 

































 


























Fig. (2). Adversarial autoencoder, a type of autoencoder [45]. (A higher resolution / colour version of this figure is available in the electronic
copy of the article).

representation on a model designed using synthetic accessi-
bility score and QED drug-likeness score [44]. New chemi-
cal structures are produced by adversarial autoencoder which
is screened by the discriminative adversarial model for iden-
tification of the real structures from the generated molecules.
Thus the authenticity of the structures generated by the ad-
versarial autoencoder is high as compared to that of the vari-
ational autoencoder. New structures that are active against
the type 2 receptor of dopamine were achieved by a combina-
tion of in silico model with autoencoders. Furthermore, com-
pounds possessing putative anticancer properties were also
predicted using a generative adversarial network (GAN) [31].
2.2. Synthesis of Drugs using AI
The synthesis of a drug is very important in drug chemis-
try. Nevertheless, the available chemical spaces are limited
by stringent synthetic routes. The retrosynthetic procedure is
a relevant method in drug synthesis. The retro-synthetic
pathway has been modified through the application of AI
[45]. The prediction for forwarding synthesis has been car-
ried out by the machine learning approach, which analyses
the synthetic methods after analysis of the retrosynthetic
pathways. The synthetic route of the drug is designed after
its identification and the major influencing factor is the time
required for finding the appropriate path. The backward syn-
thetic route is chalked out in order to find a suitable precur-
sor for the drug molecule through Monte Carlo tree search
(MCTS) [46]. The earlier method of computer-assisted syn-
thesis planning (CASP) did not gain popularity as the algo-
rithm depended on human knowledge for inputs. Alternately,
the empirical data is used by the machine learning process
which aids in the selection of a random step along with ana-
lysing the feasible position for branching. Predefined transfor-
mation rules are adopted which relate the target molecule to the
particular precursors. Thus the most probable retro-synthetic route
can be predicted by the AI. Three different neural networks were
combined with CASP to design the 3N-MCTS method where each
network was assigned three different chores, an expansion node,
rollout node followed by an update node.
The algorithm explores the feasibility of altering the
molecule is analysed from 12.4 million methods of transfor-
mation in the expansion node [47]. The route is selected by
the neural networks for the most probable transformation
with maximum yield. The formation of side products can be
eliminated by finding the route with maximum selectivity.
The recurrently used transformation routes for a molecule
are selected using a slow and methodical approach by the
rollout node [48]. The analysis of a particular route is added
1822 Combinatorial Chemistry & High Throughput Screening, 2022, Vol. 25, No. 11
to the update node. The three approaches guide an individual
to find the best retro-synthetic pathway for the design of a
drug. The algorithm should also be able to perform a task
within a stipulated time frame. The MCTS was capable of
predicting retro routes for drug molecules within 5 seconds
with 20 times of enhanced speed than the conventional Mon-
te Carlo method.
Apart from designing the routes for the reaction, AI can
foretell the products and yield of the reaction by analysing
the molecular characteristics of the reaction. The results of a
complex chemical reaction were predicted by semi-empirical
methods, the Hartree-Fock method and density functional
theory (DFT) by using the method of quantum chemistry.
The experiments could also be modelled using in silico pro-
cess. The machine learning process was used for analysing
the yields of palladium catalysed Buchwald-Hartwig cou-
pling reactions for the synthesis of carbon-nitrogen bonds in
the total synthesis of drugs in pharmaceuticals [49]. The ana-
lysed values of the dipole moments and vibrational frequen-
cies were used as descriptors and the yields were obtained
from different experimental syntheses. The relation between
the yields of the product and the descriptors was analysed by
the random forest approach [50]. The algorithm was also
used for analysing the yields of different products [49].
2.2.1. Softwares
There are certain chemical codes for the synthesis of
molecules in the Chemputer software, which is operated by
Chempiler program [51]. The software has been successfully
used for the synthesis of three pharmaceutical drugs, namely
rufinamide, diphenhydramine hydrochloride and sildenafil.
The Chemical Assembly (ChASM) is a scripting language
that sends the synthetic methods using codes and chemical
descriptive languages for understanding and designing the
synthetic process [51]. The Chempiler can operate the chem-
ical synthesis using a markup language called GraphML
[52]. The synthesis of the aforementioned drugs opens a new
realm in drug synthesis with more safety and reproducibility.
The unexplored reaction space has also been explored using
chemical robots.
The reaction and the products have been predicted by a
combination of machine learning, encoded manual rules and
quantum chemical descriptors, which have been used for the
forecasting of reactions occurring in multiple steps [53].
Numerous reactions were obtained from Reaxys and fed into
a deep neural network. Another set of data was used with
failed chemical reactions. The neural network analysed the
possible reactions and ranked them accordingly. This process
aided in the identification of the major reaction product.
However, the parameters like catalysts, reaction conditions
have to be considered for future development.
2.2.1.1. Pharmacoepidemiology
The study of using the drugs by a large group of people
and its effect is termed pharmacoepidemiology. The com-
monly used AI techniques in this field are artificial neural
network (ANN), random forest (RF) and support vector ma-
chine (SVM). However, among the aforementioned three
techniques, the artificial neural network is most predomi-
nantly used [54]. Although the random forest was discovered
recently in 2001, it has gained immense popularity as the
Sahu et al.
clinical results can be predicted by scientists without in-
depth knowledge about machine learning or statistics [55].
The subtle patterns present in the complicated datasets are
identified using the support vector machine tool [56]. The
most common approach to applying AI in pharmacoepide-
miology is to use more than a single approach as the best
algorithm is complicated to choose without prior knowledge.
The maximum accuracy of an AI application depends on the
benchmark of the multiple algorithms by using ‘trial and
error’ method. The secondary data are used in selected cases
by the application of different data sources on the efficacy of
the drug, utilisation of the drug and standard treatment pro-
cedure [57]. This process is cheaper and easier than the use
of primary data, which requires a lot of new data. The meth-
odological studies in pharmacoepidemiology were studied
among the particularly selected articles.
2.3. Polypharmacology
The capability of certain drugs to target different proteins
simultaneously has been widely exploited and the study is
termed polypharmacology. It is an emerging tool as the de-
signed drugs exhibit low resistance and developed safety
profiles [58]. The pharmacokinetic profile of a single
polypharmacological agent can be predicted efficiently and
the negative synergistic effects or interaction between the
drugs can be reduced. The resistance to the drug can also be
overcome with polypharmacology. A common example of a
polypharmacological drug is sildenafil, commonly known as
Viagra, which was initially developed for treating hyperten-
sion and ischemic heart disease but was found to be more
potent for treating the symptoms of erectile dysfunctions.
The deep learning and AI approaches have been used for the
identification of the patterns obtained from data obtained
from multi-omics and HTS in this area [59]. The DeepVS is
a Convolutional Neural Network which analyses the results
obtained from the experiments on docking and recognises
the features required for the binding of a particular protein to
a specific ligand [60]. The structural data which describes
the complex is analysed by the Deep VS technique. A com-
parison of this particular algorithm with 40 other different
algorithms indicated that DeepVS was far more efficient.
The docking poses were analysed devoid of using manual
parameters, which made them suitable for large-scale screen-
ing. In this line, the kinase inhibitors are mainly considered
in the field of polypharmacology. The kinases are proteins
that aid in the regulation of the physiological processes and
signalling routes that get deregulated during cancers. The AI
has been used for targeting the molecules which are kinase
inhibitors. The structure-based analysis is done by KinomeX,
which has been categorised as kinome-wide pharmacology
[61]. However, the AI methods are less accurate in some
cases than that of the established methods.
2.4. Finding the Target Molecule or Properties
2.4.1. Repositioning of Drugs
The further development of an already approved drug for
increasing its efficacy and other potency is termed as drug
repositioning [62]. The complete process is as follows: iden-
tification of the compound, acquirement of the compound
and its development along with safe monitoring of the mar-
ket. The availability of the omics and bioinformatics data has
Artificial Intelligence (AI) in Drugs and Pharmaceuticals Combinatorial Chemistry & High Throughput Screening, 2022, Vol. 25, No. 11
reduced the time required for the modification of a particular
drug. The repositioning of drugs is commonly carried out
with Biovista which can correlate the diseases, molecular
targets, drugs and the routes based on the data acquired by
the response of gene expression of the different cell lines
after the ingestion of the drug. Thus the data for drug reposi-
tioning can either be hypothesis based [63] or data-based or
completely on the biological networks. The three types of
approaches are text mining approach, network-based ap-
proach and semantic approach. The propagation approach in
the network-based models works by gathering the prior data
from the various layers of the network. The clustering ap-
proach forms small groups within the huge network by find-
ing an interactive linkage between diseases and drugs. Most
of the drugs are designed to have various targets exhibiting
different relationships between the diseases and the drug
[64]. Metformin was approved as a type 2 diabetic drug,
which was also found to increase the lifespan [65]. The basic
concept of network-based model is that similar drugs have
similar targets [66]. The elements to be considered for repur-
posing of drugs are genes causing the disease, drug targets
and the particular drug, which are analysed by 9 different
network analysis: protein-protein network, gene regulatory
network, drug-target network, drug-disease network, dis-
ease-disease network, drug adverse effect network, drug-
drug network, metabolic network and target disease network.
A single drug is repurposed by the integration of different
networks to form a heterogeneous network. The drug target
is considered as a link between the drug and disease [67].
The information of the multiple networks is compiled and
analysed using a network diffusion algorithm and dimen-
sionality reduction approach called DTINet for determining
the novel targets [30]. The cyclooxygenase inhibitory effect
of chlorpropamide, telmisartan and alendronate were pre-
dicted by using the algorithm which was later experimentally
proved as competent anti-inflammatory drugs.
Another approach is the Similarity Ensemble Approach
(SEA) which is based on the method of similarity. A com-
parative study was carried out for the assembly of ligands for
each target. An arbitrary comparison is conducted for creat-
ing a distribution of the similarities. A single drug molecule
is chosen and similarity is analysed with all the ligands tar-
geting a similar protein.
2.4.2. Activity Scoring
The scoring function is used for the evaluation of the
binding interactions of the drug molecules towards the target
protein [68]. The scores created by machine learning meth-
ods are done based on the inputs of chemical features, geo-
metric features and physical force features [69]. The scores
are owed to the non-linear mapping technique which extracts
the information directly from the experimental data about the
interaction between the protein and ligand. This technique
overrules the docking-related complex physical functions
[70]. The SVM model which used the experimental data of
binding affinity from eHiTS, was found to be improved both
in terms of scoring power and screening power as compared
to the hypothesis of energy parameters like linear additives
[71]. The RF was combined with scoring function of Auto-
Dock for improving the analysis [72]. The characteristic fea-
tures of the interactions between the protein and ligands
1823
were extracted by CNN, as CNN had good image processing
ability [73]. The implementation of the 3D graph CNN mod-
el for analysing the protein-ligand interaction showed fa-
vourable co-relation with the experimental data [74]. The
deep learning method (Deep VS) can interpret the abstract
characteristics from the basic qualities like the charge on the
atom, type of atoms and distance between the atoms [60].
Since the information is extorted from the image of the bind-
ing interaction of protein and ligand by CNN the accuracy is
more defined.
2.4.3. Virtual screening
The search for the bioactive molecules from different
sources like the chemical libraries which are commercially
viable or collections from the range of in-house compounds
through the application of software and algorithm is termed
as virtual screening. It is an approach to eliminate the unre-
quired scaffolds while identifying the appropriate drug [75,
76]. The three types of virtual screening techniques for dock-
ing studies are machine learning methods [77], pharmaco-
phore based [78] and similarity searching methods [79]. The
virtual screening for molecular docking can be both ligand-
based and structure-based virtual screening. However, the
evaluation process of the parameters like entropy and solva-
tion effects are not accurate which in turn hindered the accu-
rate analysis of binding affinities using scoring function of
the docking [80]. Another complication in the analysis is the
flexible structure of proteins [81]. Again, another significant
parameter like residence time is ignored which makes the
docking score ineffective for the analysis of the drug potency
as it leads to false-positive results [82]. The virtual screening
based on ligands is independent of the structural information
of the proteins, but analyses and relates the molecular char-
acteristics to their bioactive properties which mainly em-
ploys machine learning methods [75]. The output is high
with a reduced rate of false hits based on its low error, strong
capability of feature extraction along with excellent classifi-
cation properties [73]. The similarity between the simplified
molecular input line entry specification (SMILES) and natu-
ral language was identified using a model on a short-term
memory network in order to overcome the issue of virtual
screening of meager distribution of the active compounds
[20]. The gradient boosting trees and machine learning
methods (DNN) can filter the molecular libraries created by
RNN.
2.4.4. In Silico Analysis
2.4.4.1. Pharmacophore Modelling and Docking
An in silico drug discovery is a virtual screening method.
The commonly used methods are the pharmacophore model
and the docking model. The docking method analyses the
fitting of the ligand in the binding pocket of the receptor for
accessing the activity [83]. The most difficult part of the
docking studies was the use of solvents, flexibility of the
protein structure and the entropy of the system, [83] even
though the scoring function has been modified.
The chemical characteristics like hydrophobicity, pres-
ence of the number of functional groups that can be easily
ionised, presence of hydrogen bonding groups are considered
and geometrically analysed as a pharmacophore group for
investigating the interaction between the drug molecule and
1824 Combinatorial Chemistry & High Throughput Screening, 2022, Vol. 25, No. 11
the receptor [84]. The pharmacophore model is obtained
using either a receptor-ligand complex or a simple receptor.
Earlier studies used mainly ligand-based pharmacophores as
detailed information about the protein structure was unavail-
able. The shape of the binding site can be included by con-
sidering the exclusion volume [85]. The 3D model of the
pharmacophore is produced and the drug molecule which has
similarity with the generated structure is explored from with-
in the large chemical database. The database creates a fit
score that exhibits the alignment between the centre of the
model and the ligand structure. The scaffold hopping process
is also studied through these models for searching chemo-
types with the appropriate geometry and interactions [86].
Antimycobacterial agents were identified by the utiliza-
tion of both docking and pharmacophore modelling studies.
The results are standardised by the initial screening of phar-
macophores which was later confirmed by docking. An en-
zyme required for the biosynthesis of the lipid pathway is
Mtb 7.8-diaminopelargonic acid aminotrasferase (BioA) was
studied by both the docking and pharmacophore studies for
producing a receptor-based pharmacophore [87]. 25 different
functionalities like 9 H bonds, 9 hydrophobic bonds and 7
acceptors of H-bonds were considered and used for identifi-
cation of the drug from 4.5 million compounds using the
Enamine REAL database. The suitable compounds were
allowed to dock to BioA protein using CDOCKER [88].
Thus 45 potent molecules were identified and 17 compounds
were validated. The final selection was carried out for the
drug which could invade and enter the waxy and thick lipid
layer of the mycobacterium. Thus the potent compound was
{(Z)-N-(2-isopropoxyphenyl)-2-oxo-2-[(3-(trifluoromethyl)-
cyclohexyl) amino] acetimidic acid}which was a potent Bi-
oA inhibitor [89].
2.4.4.2. Physicochemical Properties
The failure related to drug design can be inhibited by the
initial identification of the negative chemical and physical
properties. The solubility of the drug molecules was fore-
casted by CNN-ANN by analysis of the molecular graph.
The hydrophilic groups responsible for the solubility of a
molecule were identified for accurate prediction [90]. An-
other method predicted the solubility of the molecules by
using convolutional embedding based on molecular tensor,
which analysed the characteristics at the atomic level using a
molecular graph [91]. The pharmacokinetic properties of the
drug were evaluated by relating the absorption of the oral
drug with the Caco-2 permeability coefficient [92].
2.4.4.2.1. Adsorption, Distribution, Metabolism, Excretion
and Toxicology (ADME/Tox)
The process by which the drug gets absorbed in the
bloodstream after administration into the system is termed
absorption. The pharmacokinetic factor which indicates the
degree of absorption is called bioavailability. The absorption
properties of a molecule can be standardised by analysing
the bioavailability of a molecule. Thus the bioavailability of
the molecule was analysed with the molecular properties and
structural fingerprints of 1014 molecules using MLR model
[93]. The molecular properties were selected by using the
method of genetic function approximation to obtain the ap-
proximate output. The ratio of the dose of the drug in vivo to
Sahu et al.
the concentration of the plasma at the steady-state is termed
as the distribution of the drug at a steady-state (VDss). The
capability of the distribution of the drug is given by VDss
and the analysis of the value of VDss aids in the modifica-
tion of the pharmacokinetic properties. PLS and Random
Forest (RF) models were generated for 1096 molecules for
analysing the VDss properties [94]. The administered drug
moves through the metabolic system or might produce toxic
metabolites. The metabolic stability of a molecule is a signif-
icant parameter for analysing the accurate site of metabo-
lism.
2.4.4.3. In Silico ADME-PK Modelling
The drug is designed by considering the experimental
endpoints like permeability, metabolic stability, transported
mediated efflux, CYP inhibition and solubility according to
the in silico ADME-modelling. A model of in silico micro-
somal stability is available at Genentech, while another
model representing in silico solubility is available at Astra-
Zeneca. The ADME/Tox has been predicted using 2D mo-
lecular descriptors and different modelling processes. The
time-dependent CYP inhibition is a certain type of model
endpoint which is challenging to predict [95]. Similarly, mi-
tochondrial toxicity is another parameter that is difficult to
predict as the toxicity can be based on different mechanisms
of cytotoxicity [96]. The application of AI in ADME/Tox
can be used in the pharmaceutical industries for selecting the
proper drug which aids in the streamlining of the particular
drug for in vivo and in vitro assays. The ADME can be ap-
plied to nanomaterials. The main advantage of the DNN al-
gorithm is that it can predict the chemical fingerprints more
accurately as compared to that of ML which was established
by Merck and the University of Toronto [33, 37]. The DNN
models also analysed the hERG inhibition and solubility of
the drug in water. The endpoints are co-related by using mul-
titask models using similar compounds [97, 98]. An hERG
model with fingerprint-based descriptors is shown in Fig.
(3). The blue colour indicates the absence of inhibition, the
orange colour indicates a weak inhibition, while the red col-
our represents strong inhibition [99].
As previously mentioned, DNN is mainly based on
SMILES instead of chemical descriptors and uses physico-
chemical properties like logD. The novel representations like
the graph convolution conducted by DNN are more meaning-
ful as compared to the depictions by the fingerprinting meth-
od, which are very complex to interpret [98]. The complex in
vivo ADME/Tox data can be interpreted and modelled by
DNN. Noise causes erroneous results in Deep learning as the
in vivo endpoints are mostly noisy. Additionally, nephrotoxici-
ty and hepatotoxicity can be identified with DNN.
Fig. (3). hERG inhibition model [99].
Artificial Intelligence (AI) in Drugs and Pharmaceuticals
Fig. (4). Alteration of half-life depending on the lipophilicity of the drugs by MMP [97].
2.4.5. MMP and ADME Models
The structures of the compounds have to be prefinalised
in ADME models. Thus the matched molecular pair (MMP)
analysis was paired with ADME models [100]. The pair of
molecules in MMP undergoes an endpoint variation if sub-
jected to a simple structural alteration which is represented
as a particular chemical transform. A specific property can
be modified by studying the chemical transformation of all
the molecular pairs.
An example of MMP change is depicted in Fig. (4), where it
has been shown that a single structural alteration can be de-
picted by various structural transforms.
The allometric principles were used for the analysis of
the half-life of the drug with the number of doses [101]. The
half-life of the C1/C2 pair was enhanced by 0.37 h by the
introduction of a fluorine atom. Additionally, although the
in vivo CLu exhibited a double-fold enhancement, there was
no considerable alteration in the doses based on the increased
half-life in the C2. The transformation of C3/C4 showed a
decreased half-life due to the addition of polar functional
groups. Thus the significance of the half-life can be under-
stood by a comparison between the C2 and C4. Although the
in vivo CLu of C4 is increased 5 times than that of C2, the
doses cannot be predicted well based on their short half-life.
The MMP database is also used for the identification of
unexpected characteristics in common fragments. The heat
map demonstrates the alteration in the parameters (passive
permeability, HLM clearance and P-gp efflux) for all six-
membered aromatic rings from phenyl in the database of
Pfizer. It was found that 4-pyridazyl was a better replace-
ment considering HLM but it leads to an enhancement of p-
gp efflux. The basic point to be considered during the appli-
cation of the MMP database is that for a particular alteration
in the structure, the endpoint value will also be similar and is
independent of the other part of the molecule, as in the case
of log D.
Combinatorial Chemistry & High Throughput Screening, 2022, Vol. 25, No. 11 1825
The transformation of a specific functional group, for in-
stance, a cyano group attached to an alkyl group, will be
hugely different than that of a cyano group attached to a
phenyl ring. This effect is called contextualisation. The
MMP process recognises the specific effect of a particular
molecule and applies it to a series of similar molecular struc-
tures, which may lead to errors. Thus the statistical parame-
ters should be accounted for while analysing the MMP trans-
forms [102]. Thus the statistical technique of drug design can
be implemented accurately using MMP tools. Thus MMP
method allows the development from model-based analysis
to the formulation of ideas.
The MMP methods have also collaborated with the
QSPR model. The core molecule and the side chains are
fragmented and organised to create a SAR table. The blank
cells in the table represent all the virtual compounds ob-
tained during the analysis. The structural transformations
obtained from either QSPR techniques or MMP databases
are used for forecasting the properties. The virtual com-
pounds can be characterised by using several endpoints,
which can be synthesised using the required routes. The data
can also be generated by the visual demonstration of the
QSPR data.
2.5. Structure of Proteins
2.5.1. Analysis of the Folding of Protein from Sequence
The dysfunction of protein causes various diseases. The
strategies for structure-based drug design can be implement-
ed by obtaining knowledge about the structure of the pro-
teins. This contributes towards the identification of the small
drug molecules which can target the desired proteins. Thus
algorithms that can forecast the 3D structure of the protein
are in demand. However, precise de novo prediction of the
3D structure of the proteins is very complex. The deep learn-
ing methods have been applied to analyse the torsion angle
of the backbone [103], the secondary structure of the protein
and contacts of the proteins [104]. The 1D structure is com-
1826 Combinatorial Chemistry & High Throughput Screening, 2022, Vol. 25, No. 11
bined with 2D CNN for analysing the residue contacts of
protein [104]. The feature extraction process is used for un-
derstanding the relationship between the structure and se-
quence by using the architecture of deep learning.
2.5.2. Interaction Between the Protein Molecules
The reason behind many diseases can be analysed by un-
derstanding the protein-protein interactions [105]. The bind-
ing sites between two protein units constitute numerous resi-
dues which are termed the PPI interface [106]. The String
database as part of the PPI database comprises 1.4 billion
PPIs which has been achieved by both bioinformatics and
experimental methods [107]. These drug targets are diverse
from conventional drug targets like nuclear receptors, G-
protein coupled receptors, kinases and ion channels. The
inhibitors of the protein-protein Database (iPPI-DB) consist
of 18 families of PPIs which can identify 1756 inhibitors of
non-peptides [108]. The development of small drug mole-
cules will be instigated by the extension of the target space
by PPI, which behaves as a novel class of targets. The bio-
logical selectivity required for the regulatory effects can be
enhanced with the targeting PPIs, since the unfavorable ef-
fects can be decreased substantially. An example is the hin-
dering of the transport of the Cu ions within the cells by the
compound -DC_AC50. This particular compound interacts
with the interfaces of the Cu transfer and thus restrains the
proliferation of the tumour cells, while the normal somatic
cell remains unaffected [109]. The interface of the PPI
should be understood for obtaining the idea of the design of
drugs depending on the structure formed by the protein-
protein complex. There are many computational methods for
analysing the interface of the PPI, since the accurate PPI
information is inadequate. Since the PPI interface is pre-
served in templates, the template-based methods are con-
sistent. The eFindSite is a website used for the prediction of
the PPI interfaces based on template, features based on se-
quences and also residue-based for the construction of the
NBC and SVM models [110]. Again, the methods for the
docking of proteins (SymmDock and ZDOCK) in case of
two interactive proteins, which have been created on the
complementarity principle are also used for the analysis of
the PPI interface. However, the forecasting of the alteration
in the conformation of two individual proteins to transform
into a single molecule is the most difficult task. The signifi-
cant features of the sequences can be obtained from the Deep
learning techniques for the analysis of the interfaces of PPI
and have been found to be better than that of the machine
learning methods like SVM. As the concealed area of the
interface is very large, the identification of the appropriate
sites for introducing the drugs is very important. The spots
which release huge binding energy are considered hot spots
[110]. The PPI sites which are favourable for introducing the
drugs have been identified using fragment docking and direct
coupling analysis (FD-DCA) by introducing a tool for the
docking of the fragment called iFitDock. This tool can be
used for recognising the hot spots in the PPI interface. The
tiny hot spots were accumulated to create a binding site for
the drug molecule. The effective binding sites for the pro-
teins were analysed using the scoring function depending on
the conservative evolutionary level. Thus the hot spots in the
PPI interfaces are effective drug targets.
Sahu et al.
2.6. Clinical Trial Design
The complexity of clinical trials like monitoring of pa-
tients and detection of the clinical endpoints has been re-
duced by the introduction of AI in this arena. Different sen-
sors can be used for recording the body functions, medicine
doses and response to medicines of selected patients. The
Deep Learning and Machine Learning methods can be used
for the analysis of these data which aids in the generation of
disease diaries and becomes specific to the expression of the
disease in a patient. The data points for the identification of
endpoints are more reliable. The AI technique has also been
used for endpoint detection based on images [111]. The
smallest doses for reducing the brain tumours were predicted
along with decreasing the side effects associated with the
chemotherapy doses, by the application of a deep reinforce-
ment learning algorithm [112]. The system investigated the
current treatment schedule and managed the dose systemati-
cally. The system finally selects an optimal plan where the
frequency of the doses could decrease the size of the tumour
with a minimum potency. Thus the doses were decreased by
half of the original dose while the reduced amount of the
tumour size remained intact. The signs of nonadherence like
incompatibility or side effects could be identified early and
solved prior to the dropout.
2.7. Personalised Medicine
The major challenge in the discovery of an appropriate
drug is the accurate classification of the symptoms and de-
velopment of the remedy. A disease is classified based on
the histology reports by pathologists for the analysis of the
molecular marker expression like the receptors at the surface
of the cell at the mRNA or protein level. For instance, the
marker gene expression is used for the PAM50 classification
of multiple subtypes of breast cancer [113]. Although the
heterogeneity remains prevalent within the subtypes, the
numerous molecular data aids in recognition of the subtypes
of the diseases and forecast the response to a treatment pro-
cedure and also the symptoms of the disease. Molecular
Prognostic Score (mPS) is a tool which is used for the accu-
rate prediction of breast cancer in patients [114]. A meta-
analysis was carried out on 6000 breast cancer patients by
using the epidemiology process. 184 genes without any
background biological information were identified. A com-
bination of Neural Network and Random Forest classifier
was built for forecasting the survival rate with half of
METABRIC cohort [115]. Additionally, overtreatment could
also be prohibited by using the score analysis. Thus the
healthcare can be transformed into precision medicine by the
application of AI.
2.8. AI in Treating Different Diseases
2.8.1. Kinase Activity
Several characteristics should be fulfilled by a drug mol-
ecule, like highly selective towards the target, good ADME-
Tox and physicochemical properties, which make it a chal-
lenging task for optimising a specific drug molecule. Ma-
chine Learning (ML) technologies like Random Forest,
Bayesian learning and support vector machines (SVM) have
been extensively used for the identification of the drug prop-
erties. The properties can be forecasted by ML process
Artificial Intelligence (AI) in Drugs and Pharmaceuticals Combinatorial Chemistry & High Throughput Screening, 2022, Vol. 25, No. 11
through the analysis of the large databases. The compound is
standardised by ML models using the datasets for anti-
targets as well as targets. The activities are forecasted against
different kinases and the profile is selected from larger da-
tasets of different kinases. 92 different kinases were selected
from the data matrix of 130,000 compounds using binary
Bayesian QSAR models. New compounds were analysed
using these models for producing affinity fingerprints for
analysing the biological activities against the novel kinases
having sparse data points. Thus the models are modified by
uploading the new experimental data and novel inhibitors of
kinase are identified by the iterative approach of machine
learning.
Random Forest identified 200 kinases with different
properties through seeing datasets from in-house and public
domains [116]. The results obtained by RF are superior
among all machine learning methods. DNN could be com-
pared with RFF with upgraded sensitivity but degraded spec-
ificity.
2.8.2. Cardiovascular Symptoms
The speech and images are identified by a type of Ma-
chine Learning algorithm known as Deep learning using an
artificial neural network (ANN). The ANNs replicate the
neurons of the brain and it attempts to learn from the large
amount of data obtained through different experiments [117].
These algorithms and data mining process acquire the capa-
bility to identify potent drug or combinations of drugs. The
asset of the deep learning process is that it provides litheness
to the neural network architecture [118]. It possesses an
abundance of memory to work and can work appropriately
with 3D-STE data and strain imaging. The Deep learning
procedure comprises a deep neural network, recurrent neural
network and convolutional neural network, which has been
especially used in cardiovascular medicines and cardiovascu-
lar imaging. The volume in end-diastolic and end-systolic in
cardiac magnetic resonance was forecasted by the applica-
tion of a convolutional neural network. The recurrent neural
network has been used for the prediction of HF prior to the
diagnosis by the doctors and was improved than that of the
algorithm obtained from machine learning [119]. Labovitz
et al. [120] used AI for examining the adherence rate of
drugs in patients suffering an ischemic stroke. They studied
and evaluated the rate of adherence of three direct oral anti-
coagulation drugs, namely rivaroxaban, dabigatran and apix-
aban along with warfarin through plasma sampling. It was
found that the rate of adherence to the drugs was lesser than
that reported earlier. The patients were administered drug
doses recommended through AI simulations and 67% of the
patients exhibited high improvement due to optimal adher-
ence to the drugs. Thus the laboratory tests were minimised
for elderly patients, and the ingestion of the medicine was
monitored using AI.
Although the presence of multiple layers in Deep learn-
ing has delivered improved performances as compared to
SVM, it is associated with different parameters during the
non-linear analysis. This phenomenon leads to overfitting
and fails to predict, which can be modified by reducing the
concealed datasets and enhancing the size of the training data
set.
1827
2.8.3. Tuberculosis
The enhanced availability of the chemical and biological
data, development in the capacities of storage of data, the
advancement of the software and technologies for drug
screening and an increase in the accuracy of the identifica-
tion of the targets have altered the existing scenario of the
antitubercular therapeutic drugs. The computer-aided drug
design (CADD) has been applied extensively in pharmaceu-
tical research involving tuberculosis drugs. The computa-
tional drug discovery has been categorised as ligand-based
drug design (LBDD) and structure-based drug de-
sign(SBDD). Thus the data obtained from the interaction of
different ligands are used for the generation of models based
on LBDD, while the 3D structure and its binding pockets are
analysed in SBDD [121]. The data mining and docking ap-
proaches are also applied to the available TB proteome and
genome, which is analysed by the virtual screening for iden-
tification of the potent candidate from the database-, the
tools used for studying the SBDD and LBDD.
The FtsZ propels the cell division and is an established
Mtb target [122]. The in silico method was applied to the
FtsZ comprising of prediction of the binding site, 3D-QSAR,
MD simulation and docking. This protein was targeted using
trisubstituted benzimidazoles using homology modelling
using S. aures FtsZ as the template for acquiring the GDP-
bound structure. The GDP binding site was recognised using
proFunc and the selected drugs were allowed to dock using
Mtb FtsZ model applying AutoDock. The orientation of the
cyclohexyl group in the benzimidazole scaffold was ana-
lysed using MD simulation studies to select the most hydro-
philic pocket, while the hydrophilic part was identified for
the carbamate group present in FtsZ. Thus the stabilisation of
the binding of the ligand and inhibition of Mtb FtsZ was
studied by the in silico analysis [122].
A combination of the ML algorithm and AI was used for
the identification of the resistant or susceptible characteris-
tics of single nucleotide variations (SNV) towards TB and
forecasting the resistance towards the mutations [123]. The
mutations were recognized which lead to the drug resistance
in M.tb using ANN, SVM, naive Bayes (NB) and k nearest
neighbour (kNN): the four different ML algorithms. The
models were generated for genes associated with the first-
line TB drugs like pyrazinamide, rifampicin, fluoroquin-
olones and isoniazid. The studies were directed to recognise
the structure-based and sequence effect of these mutations
for individual target genes. The susceptible or resistant fea-
ture of the mutation was spotted using a characteristic selec-
tion method. The alteration in the amino acid residues lead-
ing to a change in the properties of the mutant and wild-type
proteins was used as input for the model. The models were
88% accurate, where the polarity and hydrophobic properties
were significant parameters in the models. Thus the drug-
associated mutations were studied.
2.8.4. Cancer
The field of anti-cancer drug development has been ex-
tensively influenced by AI methods. There is a relationship
between the activity of the drug and the genomic variability
of the cancer cells. The integration of the Machine Learning
and screening data was conducted to form a Random Forest
1828 Combinatorial Chemistry & High Throughput Screening, 2022, Vol. 25, No. 11
Fig. (5). Structures of sensitive anticancer drugs.
model which analysed the performance of the anticancer
drug depending on the state of mutation of the cancer cell
genome [124]. Another model named elastic net regression
was developed by using the ML process to study the sensi-
tivity of the drug [125]. Thus the sensitivity of drugs was
studied for patients with gastric cancer with 5-FU, ovarian
cancer exposed to tamoxifen and endometrial cancer exposed
to paclitaxel (Fig. 5).
The prognosis of the patients with these drugs was low,
proving the role of AI in forecasting the sensitivity of the
drugs used against cancer. Additionally, the resistance to-
wards a cancer drug was also predicted by the AI [126]. The
tolerance and management of chemotherapy drugs were also
conducted by using AI. The optimum dose of enzalutamide
and zen-3694 was done using an AI platform called CU-
RATE.AI, which contributed to the tolerance of the therapy
[127]. The breast cancer cells with a deficiency in homologous
recombination were treated using poly ADP-ribose polymer-
ase inhibitors. The cancer cells having the defect of homolo-
gous recombination were detected with the appropriateness of
74% by a screening system using Deep learning models [128].
The effects of two drugs used during chemotherapy, namely
gemcitabine and taxol were identified by analysing the rela-
tion of the drug with the genes of the patient.
The algorithms of ML should be trained for screening the
data for producing models that can analyse the effect of a
drug combination or a new drug on the response of cancer
cell lines [129]. A large amount of data is required for the
synthesis of a new drug. These chemical data are processed
by ML to give the results for the synthesis of the drug [130].
The drug application has also been improved by deep learn-
ing technologies.
2.8.4.1. Cancer Genomics
The screening of genomic mutations between 1000 to
100000 was done for studying the genomic data for each
tumour sample from different patients suffering from cancer
[131]. The relation between the mutations and clinical phe-
notypes is a challenge in genomic medicine. The medical
literature is the basis for the clinical analysis of the genetic
variants. Thus there should be a connection between the
effective drugs, types of diseases and genomic mutations,
which is a complex procedure to be handled manually.
Hence the role of AI is significant where the sequence is
converted to a binary table. The binary table indicates the
absence or presence of any of the four bases at each of their
position. Deep learning allows multitask learning along with
Sahu et al.
single-task learning through sharing of model parts. An ac-
curate optimiser algorithm is used for analysing the differ-
ence between the actual values and the forecasted values.
Additionally, various data can be integrated through multi-
modal learning. Thus AI combines all the multilayered data.
The drug-susceptible genes are also recognised by relating
the omics data to the particular anti-cancer drugs.
2.8.5. Neurological Diseases
The development of drugs for neurological disorders is a
difficult task, especially for the identification of endpoints
and adherence control [132]. The self-monitoring of the pa-
tients is complex based on their neurological problems, diffi-
cult for the control of their nature and managing logging of
the medication routine. As an instance, an epileptic patient
succumbing to an absence seizure is unable to record the
incident. Similarly, an individual experiencing depression
also may be able to self-monitor the medications. Addition-
ally, neurological diseases cannot be generalised. The symp-
toms are specific for every other person, which makes it
challenging for treatment and diagnosis. Thus AI has been
used for designing sensors for real-time monitoring of the
patients. The accuracy in the field of medicine was intro-
duced by the use of Deep learning algorithms. The automat-
ed CAD system has been used for epilepsy, Alzheimer’s
disease and Parkinson’s disease. The EEG signals help in
the identification of seizure and diagnosis of epilepsy. The
backpropagation neural network and SVM are used as classi-
fiers. The HOS and WT are coupled with energy and entropy
characteristics for proper performances.
2.8.6. Dermatology
The dermatological problems and skin cancer has been
analysed using the CNN approach with a specificity of 90%
and sensitivity of 87% [11, 133]. The ML approach has been
used in teledermatology and dermatopathology. The scope
of developing personalised medicine has increased with the
application of ML technology. The side effects of the medi-
cine are thwarted by searching for precision drugs which are
done by using a multi-omics platform or psychosocial char-
acteristics. Numerous data points can be analysed for identi-
fying genetic biomarkers. The classification algorithm has
been applied to melanoma and non-melanoma skin cancer.
The application of AI is still in its infancy in other areas of
dermatology. The AI can be effectively used for psoriasis,
skin cancer and psoriatic arthritis, while other areas have to
be developed further.
Artificial Intelligence (AI) in Drugs and Pharmaceuticals Combinatorial Chemistry & High Throughput Screening, 2022, Vol. 25, No. 11
2.9. AI and Pharmaceutical Companies
The pharmaceutical companies have collaborated with
the AI companies for the successful application of AI in drug
discovery regimes since 2017. Thus biomarkers, diagnostics,
designing of new target molecules and recognition of drug
targets have seen many improvements [134]. A commonly
used tool in the discovery of drugs is Benevolent AI. Atom-
wise is a company dealing with AI in health care and has
collaborated with different pharmaceutical groups along with
Stanford University and Harvard University to search for
innovative drugs for 27 targets. Benevolent AI analyses the
data through text mining by scanning through biological and
genetic information to have an insight into the relation. Thus
graphs containing detailed information of dynamic maps and
over a billion relationships are created, where the complicat-
ed relationship generates the information along with recogni-
tion of new connections which can provide the basis for new
theories. The human analysis on certain occasions leads to
bias interpretation, while the AI uses scientific data and un-
biased analysis. The drug discovery in phenotypes is made
by a company called Exscientia. Similarly, numerate is an-
other remarkable AI company which deals in ligand chemis-
try. The designed drugs have also been tested for their clini-
cal efficacy and the development of the health care system.
The AI substitutes conventional human intelligence by
the application of automated algorithms in the arena of
pharmaceutical science. The application of AI in dealing
with complex diseases through the development of new
drugs in both the biotech and pharmaceutical industries has
been prevalent for the last 5 years. According to a survey
conducted by Verdict AI on the opinion of the business
houses on investing in the application of artificial intelli-
gence in pharma companies, 70% of the groups were posi-
tive in the investment due to a bright future. Another report
by Narrative Science revealed the application of AI by 61%
of the companies to identify any missing links in their novel
tactics of drug development.
2.9.1. Companies Using AI
Novel drugs for glaucoma are being developed by the
collaboration of an AI-based biopharmaceutical company
(twoXAR) and an ophthalmology company (Santen). The
potential ocular drug candidates would be discerned and
screened by the utilisation of the platform of drug discovery
through AI, cloud computing and big data by twoXAR. Thus
promising treatments for glaucoma are expected in the near
future. The antidote is based on AI which simplifies the in-
tricacy of the inclusion and exclusion characteristics regard-
ing the clinical trials by application of its natural language.
The detailed reports of the clinical trials are submitted to
them by the pharmaceutical companies, which is analysed by
the Antidote. The main asset is that the eligibility character-
istics of a patient can be entered, which can be deciphered by
the Antidote, whereby it can predict proper clinical trials.
Cancer therapies are being developed by a partnership be-
tween a biotechnology company (Genentech) and data ana-
lyst company (GNS Healthcare). The ML approach and data
simulation would be used by GNS Healthcare from the data
provided by Genentech. The huge data from multiple pa-
tients are transformed into different computer models by
Reverse Engineering and Forward Simulation (REFS) by
1829
GNS Healthcare. Individual cancer treatments can be found
using the models which divulge diagnostic markers and nov-
el targets. The clinical models can be engineered in a reverse
manner which aids in the growth of the cancer cells. Thus
the responses to different drugs can be studied for the crea-
tion of a response marker for the patients.
The list of clinical trials was made feasibly in a faster
manner as compared to the traditional methods by IBM Wat-
son [135]. The patients adequate for the trials were identified
by accounting the unstructured and structured data from the
medical records, which contributed towards concluding the
significant characteristics for a specific diagnosis. The algo-
rithm for deep natural language processing and reasoning in
Watson aids the physicians to have an insight into the symp-
toms and status of the health of the patients. The software
can predict the required clinical trials for the related symp-
toms using the database while eliminating the undesired
characteristics. Ali Health is a subsidiary of Alibaba from
China, which has partnered with AstraZeneca, a British drug
manufacturer for the development of proper drugs and health
services using AI. There are multiple elderly people in China
with symptoms of diabetes and cancer, which are being
treated by the AI technology of AstraZeneca. The patients
are analysed in the ambulance with the technology so that
they can be admitted to the appropriate hospitals. The drugs
of the company could also be easily accessed by the patients.
The adherence to the drug for patients is significant for a
pharmaceutical company. The data for the adherence of
drugs were submitted by the patients according to conven-
tional methods, which has been resolved by a mobile SaaS
platform (AiCure) in New York by using an algorithm for
the identification of images. The adherence to the drug is
monitored right after the patient swallows the drug using a
cell phone by AiCure. The adherence was subsequently en-
hanced for the patients suffering from schizophrenia using
the AI method by 89.7% as compared to modified directly
used therapy (71.9%).
Another biotechnology company called Cyclica invents
drugs through a combination of biophysics and AI by group-
ing with Bayer. They apply cloud-based technologies called
Ligand Express, which determines the polypharmacological
profiles of small drug molecules by screening against pro-
teins whose structure has been identified. The AI is used for
the verification of the effect of the screened drug on the par-
ticular target protein and analysing any associated side ef-
fects. The interaction of the protein and the drug is generated
visually. Chronic thromboembolic pulmonary hypertension
is a symptom having similarities to asthma and is not easily
recognised. Thus Merck & Co, along with Bayer, was grant-
ed AI software for the analysis of this particular symptom so
that the specific patterns could be identified by the radiolo-
gist. The image from the pulmonary vessels, cardiac and
lung perfusion were analysed by AI for generating the spe-
cific patterns. The ML technology has been extensively used
by Novartis for generating digital images of the cells, by
combining the cells possessing similar effects. The research
in Novartis utilises the images generated from the algorithms
obtained from machine learning for examining the com-
pounds which have not been tested. Additionally, Novartis
has highly been associated with the application of AI in the
field of pharmaceuticals.
1830 Combinatorial Chemistry & High Throughput Screening, 2022, Vol. 25, No. 11 Sahu et al.

Deubiquitinase (DUB) inhibitors were developed by two
companies, namely, AbbVie (a pharmaceutical company)
and Mission Therapeutics (drug-making company) for treat-
ing Alzheimer’s and Parkinson’s diseases. Both diseases are
caused due to the presence of toxic proteins which hamper
the nerve cells. The DUB prevents the degeneration of the
proteins and maintains stability. Further modifications are
underway using AI. Another company Verge Genomics has
been developing drugs by the collection of automated data
and analysis for treating diseases like Alzheimer’s and ALS.
The numerous genes causing the diseases were targeted by a
single drug. The application of AI by different pharmaceuti-
cal companies through a partnership with various AI compa-
nies has been shown in Table 2.

Table 2. Encapsulation of the collaboration of pharmaceutical companies with different AI companies.

Pharmaceutical Company AI Company Drug Development

Exscientia Metabolic-disease therapies like diabetes.

Sanofi Evaluate potential biomarkers of seasonal influenza vaccination outcomes in an

BERG
unbiased and data-driven manner.
(www. sanofi.com)
Move through multiple research studies and identify the most significant study to
Researchably
pharma stakeholders.

Roche subsidiary Genentech

GNS Healthcare Cancer treatments.
(www.gene.com)

Model to recognize unknown cancer mechanisms. Discovery of drug BPM31510

Berg Searching for drug targets and therapies for
(www.berghealth.com) diabetes and Parkinson’s disease.

BenevolentBio BenevolentAI Data obtained from sources like research papers,

patents, clinical trials and patient records to form knowledge graphs.

IBM Watson Drug discovery in immuno-oncology.

CytoReason to create a cell-based model of the trial-specific immune response.

Massachusetts Institute
Pharmaceutical Discovery and Synthesis Consortium.
of Technology
Pfizer Concerto HealthAI Study designs for therapeutics that are both pre and post-approved.
(www. pfizer.com)
Home robot for training patients on health and prescription drugs. Know about the
Catalia Health
clinical journey of the patient using artificial intelligence.

Roche
Exscientia, Owkin Diabetic macular edema
(www. roche.com)

PathAI Decode cancer pathology images through AI

IBM Watson Breast cancer clinical trial

McKinsey’s Quan-
500 clinical trial operations with machine learning around the world in real time.
tumBlack
Novartis
(www.novartis.com) MIT Pharmaceutical Discovery and Synthesis Consortium.

Application of DNN to accelerate high content screening, a key element of early

Intel
drug discovery.

University of Oxford’s Early forecasting of patient responses to treatments for inflammatory diseases, such
Big Data Institute (BDI) as multiple sclerosis (MS) and psoriasis.

Companies to develop appropriate models to predict promising compounds for the

MELLODDY
final stages of drug discovery and development.

Leverage data & AI to know about medicines are discovered, developed and com-
Microsoft
mercialized.
Table 2. Contd…
Artificial Intelligence (AI) in Drugs and Pharmaceuticals Combinatorial Chemistry & High Throughput Screening, 2022, Vol. 25, No. 11
Pharmaceutical Company AI Company
Janssen
-
(www.janssen.com)
Surgeons can detect small and hard-to-access lung nodules in premature conditions
Auris Health
Select the number of novel clinical-stage drug candidates and their extensive related
BenevolentAI
Johnson & Johnson
(www.jnj.com) WinterLight Labs
Merck (MSD) Accenture in collabora-
A cloud-based informatics research platform to improve efficiency, productivity and
tion with Amazon Web
(www.msd.com)
Services (AWS)
Abbvie
AiCure
(www.abbvie.com)
Exscientia
“In silico Drug Discov-
ery Unit.”
Google through nerves in the body. The irregular impulses associated with different condi-
GlaxoSmithKline In silico Medicine
(www.gsk.com) Alliance for AI in
healthcare (AAIH)
MELLODDY
Cloud Pharmaceuticals,
Inc.
-
Design potent in vivo active lead molecule and targeting a novel pathway for treat-
Exscientia
Universities of Strath-
clyde and Nottingham
GNS Healthcare
MIT
Amgen Owkin
(www.amgen.com)
MELLODDY
Gilead Sciences Insitro
2.10. Validation of the AI in Medicine
The AI has shown potential in predicting the medicines
for which different algorithms have been approved. Howev-
er, the rate of approval for new algorithms is very scanty as
the newly developed algorithms should meet the standards of
the clinical criteria dictated by the professional and regulato-
ry bodies. The testing and external validation are mandatory
processes for the advanced algorithms [136]. Apart from the
TRIPODChecklist as the existing model for the multivaria-
ble prediction analytical method in medicines [137]. There
1831
Drug Development
Application of AI to track the progress of skin progress over time for deep infor-
mation about the actual requirement and health of the skin.
to diagnose and treat lung cancer.
portfolio of patents.
Predicting neurodegenerative and dementia from voice samples obtained through
Janssen clinical trials.
innovation in the early stages of developing the drug.
AI-based patient monitoring platform improved adherence in an AbbVie phase 2
schizophrenia trial.
Discover small molecules selectively for around 10 disease-related targets across
undisclosed therapeutic area.
AI in drug discovery
Design implantable devices that can improve electrical signals which transmit
tions can also be detected.
Recognition of new biological targets and pathways.
Development and application of AI in healthcare to improve create more efficient
healthcare systems.
Train machine learning models on datasets from different partners. The privacy of
each partner is maintained using federated learning.
Design new small-molecule agents to GSK specified targets.
ing chronic obstructive pulmonary disease (COPD).
Use AI in synthetic chemistry.
Use AI in precision medicine.
Pharmaceutical discovery.
Pharmaceutical discovery.
Train machine learning models on datasets from multiple partners.
Designing disease models for nonalcoholic steatohepatitis (NASH). Search for
targets that affect the disease's progression and regression.
are other few established methods. In 2018, the WAVE Clin-
ical Platform was approved by U.S. Food and Drug Admin-
istration (FDA) which combined the data of the real-time
vital signs for patients. The in-house patients in the hospital
who were at risk of unstable vital signs were detected by the
algorithm. The WAVE was the primary predictive investi-
gating programme to be used for electronic health records
(EHR) and is recognised as the first AI algorithm product. It
was cleared by FDA depending on the likely evidence.
Nevertheless, the FDA approval of the advanced algorithms
1832 Combinatorial Chemistry & High Throughput Screening, 2022, Vol. 25, No. 11
in the field of clinical practice is limited as compared to that
of the analysis of diagnostic imaging. Innumerable variables
are provided as inputs to the algorithms. Thus the algorithms
are not static compared to a device or drug since the predic-
tive outcome of the algorithm may alter when additional data
may be provided as inputs. Thus new regulatory agendas
have been implemented by the FDA for fresh diagnostic pro-
cedures. A programme for FDA Biomarker Qualification
was formed for the authentication of the biomarkers for test-
ing and development of the drug.
The 5 prominent signs (saturation of oxygen, blood pres-
sure, heart rate, temperature and rate of respiration) are used
for the algorithm in WAVE and are used by the different
health systems. There are different complex ML algorithms
for imaging parameters or EHR, which are very specific and
thus cannot be generalised and used for other EHR. Addi-
tionally, the difference in the user interface and other multi-
ple limitations in the operations in a different setting of a
clinic hinder the capability of the clinical staff to respond to
the result of a predictive algorithm. Thus the predictive out-
puts can be enhanced by the identification of the EHR inputs
by the regulatory bodies. The input variables developed for
the algorithms should be highly specific for acquiring relia-
ble outputs across the organisation. The intellectual property
and proprietary interests of the developers of the algorithms
should be made transparent by the regulators. The data for
the algorithms should be taken from multi-ethnic population
and should not be based on the data of a single institution
[138]. Thus data from extensive populations are required for
training the algorithms.
There should be audits for the predictive algorithm after
the approval from the FDA, similar to the approved drugs
after clinical trials, which undergo scrutiny after the market-
ing of the drugs. The alteration in the predictive output can
be accounted for through this technique as the tools for deep
learning algorithms will consider new variables with the
progress of time. The systematic biases can be alleviated
through continuous audits. The algorithmic analysis should
be carried out for both anonymous and synthetic data. The
audits after marketing should be conducted by the regulatory
boards considering the intellectual property.
CONCLUSION AND FUTURE PERSPECTIVES
The progress of AI is in its third wave with the applica-
tion of deep learning and machine learning approaches. The
performance of AI is superior to humans in the field of im-
age identification, voice identification and processing of nat-
ural languages. AI has shown a huge advancement in the
initial phases in the arena of drug discovery. It has been ex-
tensively used in studying the pharmacokinetic properties,
recognition of the drug target, standardisation of the synthet-
ic methods, structuring of the clinical trials and forecasting
the toxicity of a drug. The AI application has been made
popular by different pharmaceutical companies. A Kaggle
competition was organised by Merck to accurately predict
the molecular properties of drugs. The winners lacked spe-
cific knowledge of the domain and had no expertise in the
medicinal field. However, they solved the problem using
multitask model.
Sahu et al.
The main hurdle in the application of AI in new drug dis-
covery is the dearth of problem-specific, high-quality data.
This stands as a hindrance to the AI-assisted drug discovery
module. The AI application in the field of imaging is accu-
rate as each of the data points is minute. However, the appli-
cation of AI in discovering a novel drug is still not adequate.
This is mainly because the experimental conditions for gen-
erating the data points in very complex and the biological
systems affected by the drug are also very complicated. The
results vary depending on different experimental conditions
and the data available for the drug discovery is very small.
Thus both the quantity and quality of data need improvement
for proper application of the AI in quest of new drugs. A
huge number of precise Kd values along with a crystal struc-
ture would aid in the docking and scoring problem solving
and thus improving the health of the individuals. Thus data
sharing is a significant endeavour, which is lacking between
the pharmaceutical industries. Small initiatives were put
forth by a pharmaceutical company called Pistoia in this re-
gard, which has to be embraced by all the pharmaceutical
company to make AI application in drug discovery a big
success.
Additionally, the format of the data is different from dif-
ferent companies, which demands a unified format. Thus
algorithms have to be processed for managing data in diverse
formats. The property of a drug has been analysed using low
data by an algorithm developed by Stanford University
called one-shot learning. New classes of drugs are identified
by the application of standard one-shot learning and their
characteristics are studied and predicted in the new experi-
mental system. The images are encoded by the application of
the convolutional layers into continuous vectors by the deep
one-shot learning system. The nature of the molecules can be
studied by this technique when introduced in a new molecu-
lar scaffold, by providing new data points. Thus one-shot
methods have to be further developed for the localisation of
objects with the restricted amount of data.
Another model called transfer learning can decipher the
sparse data, which was developed by the Schneider group at
ETH, Zurich. The challenges encountered with the scarce
data in the field of drug discovery were overcome by another
branch of the ML process called transfer learning. The ac-
tivity of the drug along with the molecular properties can be
estimated by this method with small available data sets. The
PPAR and PXR inhibitors were designed de novo by the
transfer learning method. However, the experimental aspect
of this field still remains to be explored. The output of the
transfer learning process requires a standard metric for eval-
uation, instead of judging it based on the decrease of errors
or enhancement of accuracy. The low data size is another
challenging arena in the transfer learning process. The major
hurdle is to quantify the similarity between two different
drug activities since the relation is more significant than that
of the data size. Additionally, the network structure design is
also pivotal as inaccurate selection methods can lead to nega-
tive transfer. There are different rules for fine-tuning which
are empirical. Additional layers are fixed for preventing
overfitting in the case of small target data. Alternately, all
the layers are tuned finely in case of large target data.
Artificial Intelligence (AI) in Drugs and Pharmaceuticals Combinatorial Chemistry & High Throughput Screening, 2022, Vol. 25, No. 11
It is expensive to bring a drug to a market, accounting for
all the background activities besides having the probability
of failure. Thus huge investment is mandatory in the field of
drug research. AI can alter the scenario by enhancing the
success rate in drug discovery, which in turn will be benefi-
cial both in terms of the financial and human front.
CONSENT FOR PUBLICATION
Not applicable.
FUNDING
None.
CONFLICT OF INTEREST
The authors declare no conflict of interest, financial or
otherwise.
ACKNOWLEDGEMENTS
Declared none.
REFERENCES
[1] Schneider, G.; Fechner, U. Computer-based de novo design of
drug-like molecules. Nat. Rev. Drug Discov., 2005, 4(8), 649-663.
http://dx.doi.org/10.1038/nrd1799 PMID: 16056391
[2] Schneider, G.; Clark, D.E. Automated Automated de novo drug
design: Are we nearly there yet drug design: Are we nearly there
yet? Angew. Chem. Int. Ed. Engl., 2019, 58(32), 10792-10803.
http://dx.doi.org/10.1002/anie.201814681 PMID: 30730601
[3] Schneider, G.; Geppert, T.; Hartenfeller, M.; Reisen, F.; Klenner,
A.; Reutlinger, M.; Hähnke, V.; Hiss, J.A.; Zettl, H.; Keppner, S.;
Spänkuch, B.; Schneider, P. Reaction-driven de novo design, syn-
thesis and testing of potential type II kinase inhibitors. Future Med.
Chem., 2011, 3(4), 415-424.
http://dx.doi.org/10.4155/fmc.11.8 PMID: 21452978
[4] McCarthy, J.; Hayesm, P.J. Some Philosophical Problems from
Standpoint of Artificial Intelligence. In: Machine Intelligence; Ed-
inburgh University Press: Edinburgh, 1969; pp. 463-502.
[5] Qian, N.; Sejnowski, T.J. Predicting the secondary structure of
globular proteins using neural network models. J. Mol. Biol., 1988,
202(4), 865-884.
http://dx.doi.org/10.1016/0022-2836(88)90564-5 PMID: 3172241
[6] Hammett, L.P. The effect of structure upon the reactions of organic
compounds. Temperature and solvent influences. J. Chem. Phys.,
1936, 4, 613-617.
http://dx.doi.org/10.1063/1.1749914
[7] Hansch, C.; Fujita, T. ρ-σ-π Analysis. A method for the correlation
of biological activity and chemical structure. J. Am. Chem. Soc.,
1964, 86, 5710.
http://dx.doi.org/10.1021/ja01078a623
[8] Radchenko, E.V.; Dyabina, A.S.; Palyulin, V.A.; Zefirov, N.S.
Prediction of human intestinal absorption of drug compounds.
Russ. Chem. Bull., 2016, 65, 576-580.
http://dx.doi.org/10.1007/s11172-016-1340-0
[9] Jayaram, H.N.; Gharehbaghi, K.; Jayaram, N.H.; Rieser, J.; Krohn,
K.; Paull, K.D. Cytotoxicity of a new IMP dehydrogenase inhibitor,
benzamide riboside, to human myelogenous leukemia K562 cells.
Biochem. Biophys. Res. Commun., 1992, 186(3), 1600-1606.
http://dx.doi.org/10.1016/S0006-291X(05)81591-8 PMID:
1354960
[10] Martin, Y.C.; Holland, J.B.; Jarboe, C.H.; Plotnikoff, N. Discrimi-
nant analysis of the relationship between physical properties and
the inhibition of monoamine oxidase by aminotetralins and ami-
noindans. J. Med. Chem., 1974, 17(4), 409-413.
http://dx.doi.org/10.1021/jm00250a008 PMID: 4830537
1833
[11] Kneller, D.G.; Cohen, F.E.; Langridge, R. Improvements in protein
secondary structure prediction by an enhanced neural network. J.
Mol. Biol., 1990, 214(1), 171-182.
http://dx.doi.org/10.1016/0022-2836(90)90154-E PMID: 2370661
[12] Weinstein, J.N.; Kohn, K.W.; Grever, M.R.; Viswanadhan, V.N.;
Rubinstein, L. V.; Monks, A.P.; Scudiero, D.A.; Welch, L.; Kout-
soukos, A.D.; Chiausa, A.J.; Paull, K.D. Neural computing in can-
cer drug development: Predicting mechanism of action. Science,
1992, 258, 447-451.
[13] Schneider, G. Generative models for artificially-intelligent molecu-
lar design. Mol. Inform., 2018, 37(1-2), 1880131.
http://dx.doi.org/10.1002/minf.201880131 PMID: 29442446
[14] Ho, T.K. Random decision forests. Proc. Int. Conf. Doc. Anal.
Recognition, ICDAR, 1995, pp. 278-282.
[15] Guenther, N.M.S. Support Vector Machines (SVM) Support Vector
Machines (SVM). Gesture, 2001, 23, 349-361.
[16] Lohmann, R.; Schneider, G.; Wrede, P. Structure optimization of
an artificial neural filter detecting membrane-spanning amino acid
sequences. Biopolymers, 1996, 38(1), 13-29.
http://dx.doi.org/10.1002/(SICI)1097-0282(199601)38:1<13::AID-
BIP2>3.0.CO;2-Z PMID: 8679941
[17] Mayr, A.; Klambauer, G.; Unterthiner, T.; Hochreiter, S. DeepTox:
Toxicity prediction using deep learning. Front. Environ. Sci., 2016,
3, 80.
http://dx.doi.org/10.3389/fenvs.2015.00080
[18] Dahl, G.E.; Jaitly, N.; Salakhutdinov, R. Multi-Task Neural Net-
works for QSAR Predictions. arXiv:1406.1231v1, 2014.
[19] Gómez-Bombarelli, R.; Wei, J.N.; Duvenaud, D.; Hernández-
Lobato, J.M.; Sánchez-Lengeling, B.; Sheberla, D.; Aguilera-
Iparraguirre, J.; Hirzel, T.D.; Adams, R.P.; Aspuru-Guzik, A. Au-
tomatic chemical design using a data-driven continuous representa-
tion of molecules. ACS Cent. Sci., 2018, 4(2), 268-276.
http://dx.doi.org/10.1021/acscentsci.7b00572 PMID: 29532027
[20] Segler, M.H.S.; Kogej, T.; Tyrchan, C.; Waller, M.P. Generating
focused molecule libraries for drug discovery with recurrent neural
networks. ACS Cent. Sci., 2018, 4(1), 120-131.
http://dx.doi.org/10.1021/acscentsci.7b00512 PMID: 29392184
[21] Putin, E.; Asadulaev, A.; Ivanenkov, Y.; Aladinskiy, V.; Sanchez-
Lengeling, B.; Aspuru-Guzik, A.; Zhavoronkov, A. Reinforced
Adversarial Neural Computer for de novo Molecular Design. J.
Chem. Inf. Model., 2018, 58(6), 1194-1204.
http://dx.doi.org/10.1021/acs.jcim.7b00690 PMID: 29762023
[22] Reymond, J.L.; Van Deursen, R.; Blum, L.C.; Ruddigkeit, L.
Chemical space as a source for new drugs. MedChemComm, 2010,
1, 30-38.
http://dx.doi.org/10.1039/c0md00020e
[23] Paul, D.; Sanap, G.; Shenoy, S.; Kalyane, D.; Kalia, K.; Tekade,
R.K. Artificial intelligence in drug discovery and development.
Drug Discov. Today, 2021, 26(1), 80-93.
http://dx.doi.org/10.1016/j.drudis.2020.10.010 PMID: 33099022
[24] Duran, O.; Rodriguez, N.; Consalter, L.A. Neural networks for cost
estimation of shell and tube heat exchangers. Expert Syst. Appl.,
2009, 36, 7435-7440.
http://dx.doi.org/10.1016/j.eswa.2008.09.014
[25] Park, Y.; Goto, D.; Yang, K.F.; Downton, K.; Lecomte, P.; Olson,
M.; Mullins, C.D. A literature review of factors affecting price and
competition in the global pharmaceutical market. Value Health,
2016, 19, A265.
http://dx.doi.org/10.1016/j.jval.2016.03.816
[26] de Jesus, A. AI for Pricing – Comparing 5 Current Applications.
EMERJ, 2019, Available from: https://emerj.com/ai-sector-
overviews/ai-for-pricing-comparing-5-current-applications/
[27] Chan, H.C.S.; Li, Y.; Dahoun, T.; Vogel, H.; Yuan, S. New binding
sites, new opportunities for GPCR drug discovery. Trends Bio-
chem. Sci., 2019, 44(4), 312-330.
http://dx.doi.org/10.1016/j.tibs.2018.11.011 PMID: 30612897
[28] Cavasotto, C.N.; Phatak, S.S. Homology modeling in drug discov-
ery: Current trends and applications. Drug Discov. Today, 2009,
14(13-14), 676-683.
http://dx.doi.org/10.1016/j.drudis.2009.04.006 PMID: 19422931
[29] Hayik, S.A.; Dunbrack, R., Jr; Merz, K.M., Jr. A mixed QM/MM
scoring function to predict protein-ligand binding affinity. J. Chem.
Theory Comput., 2010, 6(10), 3079-3091.
http://dx.doi.org/10.1021/ct100315g PMID: 21221417
1834 Combinatorial Chemistry & High Throughput Screening, 2022, Vol. 25, No. 11
[30] Smith, J.S.; Isayev, O.; Roitberg, A.E. ANI-1: an extensible neural
network potential with DFT accuracy at force field computational
cost. Chem. Sci. (Camb.), 2017, 8(4), 3192-3203.
http://dx.doi.org/10.1039/C6SC05720A PMID: 28507695
[31] Zhang, Y.J.; Khorshidi, A.; Kastlunger, G.; Peterson, A.A. The
potential for machine learning in hybrid QM/MM calculations. J. [49]
Chem. Phys., 2018, 148(24), 241740.
http://dx.doi.org/10.1063/1.5029879 PMID: 29960374
[32] Bai, F.; Morcos, F.; Cheng, R.R.; Jiang, H.; Onuchic, J.N. Elucidat- [50]
ing the druggable interface of protein-protein interactions using
fragment docking and coevolutionary analysis. Proc. Natl. Acad.
Sci. USA, 2016, 113(50), E8051-E8058.
http://dx.doi.org/10.1073/pnas.1615932113 PMID: 27911825 [51]
[33] Wang, S.; Sun, S.; Li, Z.; Zhang, R.; Xu, J. Accurate de novo pre-
diction of protein contact map by ultra-deep learning model. PLOS
Comput. Biol., 2017, 13(1), e1005324.
http://dx.doi.org/10.1371/journal.pcbi.1005324 PMID: 28056090
[34] Luo, Y.; Zhao, X.; Zhou, J.; Yang, J.; Zhang, Y.; Kuang, W.; Peng, [52]
J.; Chen, L.; Zeng, J. A network integration approach for drug-
target interaction prediction and computational drug repositioning
from heterogeneous information. Nat. Commun., 2017, 8(1), 573.
http://dx.doi.org/10.1038/s41467-017-00680-8 PMID: 28924171 [53]
[35] Kadurin, A.; Aliper, A.; Kazennov, A.; Mamoshina, P.; Vanhaelen,
Q.; Khrabrov, K.; Zhavoronkov, A. The cornucopia of meaningful
leads: Applying deep adversarial autoencoders for new molecule
development in oncology. Oncotarget, 2017, 8(7), 10883-10890. [54]
http://dx.doi.org/10.18632/oncotarget.14073 PMID: 28029644
[36] Kadurin, A.; Nikolenko, S.; Khrabrov, K.; Aliper, A.; Zhavor-
onkov, A. druGAN: An advanced generative adversarial autoen-
coder model for de novo generation of new molecules with desired
molecular properties in silico. Mol. Pharm., 2017, 14(9), 3098-
3104. [55]
http://dx.doi.org/10.1021/acs.molpharmaceut.7b00346 PMID:
28703000
[37] Ma, J.; Sheridan, R.P.; Liaw, A.; Dahl, G.E.; Svetnik, V. Deep
neural nets as a method for quantitative structure-activity relation- [56]
ships. J. Chem. Inf. Model., 2015, 55(2), 263-274.
http://dx.doi.org/10.1021/ci500747n PMID: 25635324
[38] Kearnes, S.; Goldman, B.; Pande, V. Modeling industrial ADMET
data with multitask networks. arXiv, 1606, 08793v3., 2016. [57]
[39] Schneider, P.; Schneider, G. De novo De novo design at the edge of
chaos. J. Med. Chem., 2016, 59(9), 4077-4086.
http://dx.doi.org/10.1021/acs.jmedchem.5b01849 PMID: 26881908
[40] Gupta, A.; Müller, A.T.; Huisman, B.J.H.; Fuchs, J.A.; Schneider, [58]
P.; Schneider, G. Generative recurrent networks for de novo drug
design. Mol. Inform., 2018, 37, 1700111.
http://dx.doi.org/10.1002/minf.201700111
[41] Müller, A.T.; Hiss, J.A.; Schneider, G. Recurrent neural network [59]
model for constructive peptide design. J. Chem. Inf. Model., 2018,
58(2), 472-479.
http://dx.doi.org/10.1021/acs.jcim.7b00414 PMID: 29355319
[42] Merk, D.; Friedrich, L.; Grisoni, F.; Schneider, G. De novo design
of bioactive small molecules by artificial intelligence. Mol. Inform., [60]
2018, 37(1-2), 1700153.
http://dx.doi.org/10.1002/minf.201700153 PMID: 29319225
[43] Hessler, G.; Baringhaus, K.H. Artificial intelligence in drug design.
Molecules, 2018, 23(10), 2520. [61]
http://dx.doi.org/10.3390/molecules23102520 PMID: 30279331
[44] Bickerton, G.R.; Paolini, G.V.; Besnard, J.; Muresan, S.; Hopkins,
A.L. Quantifying the chemical beauty of drugs. Nat. Chem., 2012,
4(2), 90-98.
http://dx.doi.org/10.1038/nchem.1243 PMID: 22270643
[45] Klucznik, T. Efficient syntheses of diverse, medicinally relevant [62]
targets planned by computer and executed in the laboratory. Chem.,
2018, 4, 522-532.
http://dx.doi.org/10.1016/j.chempr.2018.02.002
[46] Browne, C.B. A Survey of monte Carlo tree search methods. IEEE [63]
T. Comp. Intel. Al, 2017, 4, 1-43.
[47] Segler, M.H.S.; Waller, M.P. Neural-symbolic machine learning
for retrosynthesis and reaction prediction. Chemistry, 2017, 23(25),
5966-5971. [64]
http://dx.doi.org/10.1002/chem.201605499 PMID: 28134452
[48] Silver, D.; Huang, A.; Maddison, C.J.; Guez, A.; Sifre, L.; van den
Driessche, G.; Schrittwieser, J.; Antonoglou, I.; Panneershelvam,
Sahu et al.
V.; Lanctot, M.; Dieleman, S.; Grewe, D.; Nham, J.; Kalchbrenner,
N.; Sutskever, I.; Lillicrap, T.; Leach, M.; Kavukcuoglu, K.; Grae-
pel, T.; Hassabis, D. Mastering the game of Go with deep neural
networks and tree search. Nature, 2016, 529(7587), 484-489.
http://dx.doi.org/10.1038/nature16961 PMID: 26819042
Chuang, K. V.; Keiser, M.J. Predicting reaction performance in C–
N cross-coupling using machine learning. Science. Science, 2018,
362, 186-190.
Maryasin, B.; Marquetand, P.; Maulide, N. Machine learning for
organic synthesis: Are robots replacing chemists? Angew. Chem.
Int. Ed. Engl., 2018, 57(24), 6978-6980.
http://dx.doi.org/10.1002/anie.201803562 PMID: 29701305
Steiner, S.; Wolf, J.; Glatzel, S.; Andreou, A.; Granda, J.M.; Kee-
nan, G.; Hinkley, T.; Aragon-Camarasa, G.; Kitson, P.J.; Angelone,
D.; Cronin, L. Organic synthesis in a modular robotic system driv-
en by a chemical programming language. Science, 2019, 363,
eaav2211.
Fuhrman, J.A.; Schwalbach, M.S.; Stingl, U. Proteorhodopsins: An
array of physiological roles? Nat. Rev. Microbiol., 2008, 6(6), 488-
494.
http://dx.doi.org/10.1038/nrmicro1893 PMID: 18475306
Fooshee, D.; Mood, A.; Gutman, E.; Tavakoli, M.; Urban, G.; Liu,
F.; Huynh, N.; Van Vranken, D.; Baldi, P. Deep learning for chem-
ical reaction prediction. Mol. Syst. Des. Eng., 2018, 3, 442-452.
http://dx.doi.org/10.1039/C7ME00107J
Jones, L.D.; Golan, D.; Hanna, S.A.; Ramachandran, M. Artificial
intelligence, machine learning and the evolution of healthcare: A
bright future or cause for concern? Bone Joint Res., 2018, 7(3),
223-225.
http://dx.doi.org/10.1302/2046-3758.73.BJR-2017-0147.R1 PMID:
29922439
Couronné, R.; Probst, P.; Boulesteix, A.L. Random forest versus
logistic regression: A large-scale benchmark experiment. BMC Bio-
informatics, 2018, 19(1), 270.
http://dx.doi.org/10.1186/s12859-018-2264-5 PMID: 30016950
Huang, S.; Cai, N.; Pacheco, P.P.; Narrandes, S.; Wang, Y.; Xu, W.
Applications of Support Vector Machine (SVM) learning in cancer
genomics. Cancer Genomics Proteomics, 2018, 15(1), 41-51.
PMID: 29275361
Hennessy, S. Use of health care databases in pharmacoepidemiolo-
gy. Basic Clin. Pharmacol. Toxicol., 2006, 98(3), 311-313.
http://dx.doi.org/10.1111/j.1742-7843.2006.pto_368.x PMID:
16611207
Anighoro, A.; Bajorath, J.; Rastelli, G. Polypharmacology: Chal-
lenges and opportunities in drug discovery. J. Med. Chem., 2014,
57(19), 7874-7887.
http://dx.doi.org/10.1021/jm5006463 PMID: 24946140
Jasial, S.; Gilberg, E.; Blaschke, T.; Bajorath, J. Machine learning
distinguishes with high accuracy between pan-assay interference
compounds that are promiscuous or represent dark chemical matter.
J. Med. Chem., 2018, 61(22), 10255-10264.
http://dx.doi.org/10.1021/acs.jmedchem.8b01404 PMID: 30422657
Pereira, J.C.; Caffarena, E.R.; Dos Santos, C.N. Boosting docking-
based virtual screening with deep learning. J. Chem. Inf. Model.,
2016, 56(12), 2495-2506.
http://dx.doi.org/10.1021/acs.jcim.6b00355 PMID: 28024405
Li, Z.; Li, X.; Liu, X.; Fu, Z.; Xiong, Z.; Wu, X.; Tan, X.; Zhao, J.;
Zhong, F.; Wan, X.; Luo, X.; Chen, K.; Jiang, H.; Zheng, M.; Ki-
nome, X. KinomeX: A web application for predicting kinome-wide
polypharmacology effect of small molecules. Bioinformatics, 2019,
35(24), 5354-5356.
http://dx.doi.org/10.1093/bioinformatics/btz519 PMID: 31228181
Lotfi Shahreza, M.; Ghadiri, N.; Mousavi, S.R.; Varshosaz, J.;
Green, J.R. A review of network-based approaches to drug reposi-
tioning. Brief. Bioinform., 2018, 19(5), 878-892.
http://dx.doi.org/10.1093/bib/bbx017 PMID: 28334136
Gönen, M. Predicting drug-target interactions from chemical and
genomic kernels using Bayesian matrix factorization. Bioinformat-
ics, 2012, 28(18), 2304-2310.
http://dx.doi.org/10.1093/bioinformatics/bts360 PMID: 22730431
Klaeger, S.; Heinzlmeir, S.; Wilhelm, M.; Küster, B. The target
landscape of clinical kinase inhibitors. Mol. Cell. Proteomics,
2017, 16, S14.
Artificial Intelligence (AI) in Drugs and Pharmaceuticals Combinatorial Chemistry & High Throughput Screening, 2022, Vol. 25, No. 11
[65] Cabreiro, F.; Au, C.; Leung, K.Y.; Vergara-Irigaray, N.; Cochemé,
H.M.; Noori, T.; Weinkove, D.; Schuster, E.; Greene, N.D.E.;
Gems, D. Metformin retards aging in C. elegans by altering micro-
bial folate and methionine metabolism. Cell, 2013, 153(1), 228-
239.
http://dx.doi.org/10.1016/j.cell.2013.02.035 PMID: 23540700
[66] Yamanishi, Y.; Araki, M.; Gutteridge, A.; Honda, W.; Kanehisa,
M. Prediction of drug-target interaction networks from the integra-
tion of chemical and genomic spaces. Bioinformatics, 2008, 24(13),
i232-i240.
http://dx.doi.org/10.1093/bioinformatics/btn162 PMID: 18586719
[67] Wang, W.; Yang, S.; Zhang, X.; Li, J. Drug repositioning by inte-
grating target information through a heterogeneous network model.
Bioinformatics, 2014, 30(20), 2923-2930.
http://dx.doi.org/10.1093/bioinformatics/btu403 PMID: 24974205
[68] Huang, S.Y.; Grinter, S.Z.; Zou, X. Scoring functions and their
evaluation methods for protein-ligand docking: Recent advances
and future directions. Phys. Chem. Chem. Phys., 2010, 12(40),
12899-12908.
http://dx.doi.org/10.1039/c0cp00151a PMID: 20730182
[69] Khamis, M.A.; Gomaa, W.; Ahmed, W.F. Machine learning in
computational docking. Artif. Intell. Med., 2015, 63(3), 135-152.
http://dx.doi.org/10.1016/j.artmed.2015.02.002 PMID: 25724101
[70] Ain, Q.U.; Aleksandrova, A.; Roessler, F.D.; Ballester, P.J. Ma-
chine-learning scoring functions to improve structure-based bind-
ing affinity prediction and virtual screening. Wiley Interdiscip. Rev.
Comput. Mol. Sci., 2015, 5(6), 405-424.
http://dx.doi.org/10.1002/wcms.1225 PMID: 27110292
[71] Kinnings, S.L.; Liu, N.; Tonge, P.J.; Jackson, R.M.; Xie, L.;
Bourne, P.E. A machine learning-based method to improve dock-
ing scoring functions and its application to drug repurposing. J.
Chem. Inf. Model., 2011, 51(2), 408-419.
http://dx.doi.org/10.1021/ci100369f PMID: 21291174
[72] Wang, C.; Zhang, Y. Improving scoring-docking-screening powers
of protein-ligand scoring functions using random forest. J. Comput.
Chem., 2017, 38(3), 169-177.
http://dx.doi.org/10.1002/jcc.24667 PMID: 27859414
[73] LeCun, Y.; Bengio, Y.; Hinton, G. Deep learning. Nature, 2015,
521(7553), 436-444.
http://dx.doi.org/10.1038/nature14539 PMID: 26017442
[74] Jiménez, J.; Škalič, M.; Martínez-Rosell, G.; De Fabritiis, G. KDEEP:
Protein-ligand absolute binding affinity prediction via 3D-
convolutional neural networks. J. Chem. Inf. Model., 2018, 58(2),
287-296.
http://dx.doi.org/10.1021/acs.jcim.7b00650 PMID: 29309725
[75] McInnes, C. Virtual screening strategies in drug discovery. Curr.
Opin. Chem. Biol., 2007, 11(5), 494-502.
http://dx.doi.org/10.1016/j.cbpa.2007.08.033 PMID: 17936059
[76] Lavecchia, A.; Di Giovanni, C. Virtual screening strategies in drug
discovery: a critical review. Curr. Med. Chem., 2013, 20(23), 2839-
2860.
http://dx.doi.org/10.2174/09298673113209990001 PMID:
23651302
[77] Leelananda, S.P.; Lindert, S. Computational methods in drug dis-
covery. Beilstein J. Org. Chem., 2016, 12, 2694-2718.
http://dx.doi.org/10.3762/bjoc.12.267 PMID: 28144341
[78] Kim, K.H.; Kim, N.D.; Seong, B.L. Pharmacophore-based virtual
screening: A review of recent applications. Expert Opin. Drug Dis-
cov., 2010, 5(3), 205-222.
http://dx.doi.org/10.1517/17460441003592072 PMID: 22823018
[79] Willett, P. Similarity-based virtual screening using 2D fingerprints.
Drug Discov. Today, 2006, 11(23-24), 1046-1053.
http://dx.doi.org/10.1016/j.drudis.2006.10.005 PMID: 17129822
[80] Huang, S.Y.; Zou, X. Inclusion of solvation and entropy in the
knowledge-based scoring function for protein-ligand interactions.
J. Chem. Inf. Model., 2010, 50(2), 262-273.
http://dx.doi.org/10.1021/ci9002987 PMID: 20088605
[81] Chen, Y.C. Beware of docking! Trends Pharmacol. Sci., 2015,
36(2), 78-95.
http://dx.doi.org/10.1016/j.tips.2014.12.001 PMID: 25543280
[82] Xing, J.; Lu, W.; Liu, R.; Wang, Y.; Xie, Y.; Zhang, H.; Shi, Z.;
Jiang, H.; Liu, Y.C.; Chen, K.; Jiang, H.; Luo, C.; Zheng, M. Ma-
chine-learning-assisted approach for discovering novel inhibitors
1835
targeting bromodomain-containing protein 4. J. Chem. Inf. Model.,
2017, 57(7), 1677-1690.
http://dx.doi.org/10.1021/acs.jcim.7b00098 PMID: 28636361
[83] Halperin, I.; Ma, B.; Wolfson, H.; Nussinov, R. Principles of dock-
ing: An overview of search algorithms and a guide to scoring func-
tions. Proteins, 2002, 47(4), 409-443.
http://dx.doi.org/10.1002/prot.10115 PMID: 12001221
[84] Leach, A.R.; Gillet, V.J.; Lewis, R.A.; Taylor, R. Three-
dimensional pharmacophore methods in drug discovery. J. Med.
Chem., 2010, 53(2), 539-558.
http://dx.doi.org/10.1021/jm900817u PMID: 19831387
[85] Hein, M.; Zilian, D.; Sotriffer, C.A. Docking compared to 3D-
pharmacophores: The scoring function challenge. Drug Discov.
Today. Technol., 2010, 7, e229-e236.
http://dx.doi.org/10.1016/j.ddtec.2010.12.003
[86] Hessler, G.; Baringhaus, K.H. The scaffold hopping potential of
pharmacophores. Drug Discov. Today. Technol., 2010, 7(4), e203-
e270.
http://dx.doi.org/10.1016/j.ddtec.2010.09.001 PMID: 24103802
[87] Dassault Systèmes, BIOVIA Discovery Studio., Available from:
https://discover.3ds.com/discovery-studio-visualizer-download
[88] Wu, G.; Robertson, D.H.; Brooks, C.L., III; Vieth, M. Detailed
analysis of grid-based molecular docking: A case study of
CDOCKER-A CHARMm-based MD docking algorithm. J. Com-
put. Chem., 2003, 24(13), 1549-1562.
http://dx.doi.org/10.1002/jcc.10306 PMID: 12925999
[89] Billones, J.B.; Carrillo, M.C.O.; Organo, V.G.; Sy, J.B.A.; Clavio,
N.A.B.; Macalino, S.J.Y.; Emnacen, I.A.; Lee, A.P.; Ko, P.K.L.;
Concepcion, G.P. In silico discovery and in vitro activity of inhibi-
tors against Mycobacterium tuberculosis 7,8-diaminopelargonic ac-
id synthase (Mtb BioA). Drug Des. Devel. Ther., 2017, 11, 563-
574.
http://dx.doi.org/10.2147/DDDT.S119930 PMID: 28280303
[90] Duvenaud, D.; Maclaurin, D.; Aguilera-Iparraguirre, J.; Gómez-
Bombarelli, R.; Hirzel, T.; Aspuru-Guzik, A.; Adams, R.P. Convo-
lutional networks on graphs for learning molecular fingerprints.
Adv. Neural Inf. Process. Syst., 2015, 2, 224-2232.
[91] Coley, C.W.; Barzilay, R.; Green, W.H.; Jaakkola, T.S.; Jensen,
K.F. Convolutional Embedding of Attributed Molecular Graphs for
Physical Property Prediction. J. Chem. Inf. Model., 2017, 57(8),
1757-1772.
http://dx.doi.org/10.1021/acs.jcim.6b00601 PMID: 28696688
[92] Hubatsch, I.; Ragnarsson, E.G.E.; Artursson, P. Determination of
drug permeability and prediction of drug absorption in Caco-2
monolayers. Nat. Protoc., 2007, 2(9), 2111-2119.
http://dx.doi.org/10.1038/nprot.2007.303 PMID: 17853866
[93] Tian, S.; Li, Y.; Wang, J.; Zhang, J.; Hou, T. ADME evaluation in
drug discovery. 9. Prediction of oral bioavailability in humans
based on molecular properties and structural fingerprints. Mol.
Pharm., 2011, 8(3), 841-851.
http://dx.doi.org/10.1021/mp100444g PMID: 21548635
[94] Lombardo, F.; Jing, Y. In silico prediction of volume of distribu-
tion in humans. Extensive data set and the exploration of linear and
nonlinear methods coupled with molecular interaction fields de-
scriptors. J. Chem. Inf. Model., 2016, 56(10), 2042-2052.
http://dx.doi.org/10.1021/acs.jcim.6b00044 PMID: 27602694
[95] Zientek, M.; Stoner, C.; Ayscue, R.; Klug-McLeod, J.; Jiang, Y.;
West, M.; Collins, C.; Ekins, S. Integrated in silico-in vitro strategy
for addressing cytochrome P450 3A4 time-dependent inhibition.
Chem. Res. Toxicol., 2010, 23(3), 664-676.
http://dx.doi.org/10.1021/tx900417f PMID: 20151638
[96] Zhang, H.; Chen, Q.Y.; Xiang, M.L.; Ma, C.Y.; Huang, Q.; Yang,
S.Y. In silico prediction of mitochondrial toxicity by using GA-
CG-SVM approach. Toxicol. In Vitro, 2009, 23(1), 134-140.
http://dx.doi.org/10.1016/j.tiv.2008.09.017 PMID: 18940245
[97] Hop, P.; Allgood, B.; Yu, J. Geometric deep learning autonomous-
ly learns chemical features that outperform those engineered by
domain experts. Mol. Pharm., 2018, 15(10), 4371-4377.
http://dx.doi.org/10.1021/acs.molpharmaceut.7b01144 PMID:
29863875
[98] Kearnes, S.; McCloskey, K.; Berndl, M.; Pande, V.; Riley, P. Mo-
lecular graph convolutions: Moving beyond fingerprints. J. Com-
put. Aided Mol. Des., 2016, 30(8), 595-608.
http://dx.doi.org/10.1007/s10822-016-9938-8 PMID: 27558503
1836 Combinatorial Chemistry & High Throughput Screening, 2022, Vol. 25, No. 11
[99] Lombardo, F.; Desai, P.V.; Arimoto, R.; Desino, K.E.; Fischer, H.; [112]
Keefer, C.E.; Petersson, C.; Winiwarter, S.; Broccatelli, F. In silico
Absorption, Distribution, Metabolism, Excretion, and Pharmacoki-
netics (ADME-PK): Utility and best practices. An Industry Per- [113]
spective from the International Consortium for Innovation through
Quality in Pharmaceutical Development. J. Med. Chem., 2017,
60(22), 9097-9113.
http://dx.doi.org/10.1021/acs.jmedchem.7b00487 PMID: 28609624
[100] O’Boyle, N.M.; Boström, J.; Sayle, R.A.; Gill, A. Using matched
molecular series as a predictive tool to optimize biological activity.
J. Med. Chem., 2014, 57(6), 2704-2713. [114]
http://dx.doi.org/10.1021/jm500022q PMID: 24601597
[101] Gunaydin, H.; Altman, M.D.; Ellis, J.M.; Fuller, P.; Johnson, S.A.;
Lahue, B.; Lapointe, B. Strategy for extending half-life in drug de-
sign and its significance. ACS Med. Chem. Lett., 2018, 9(6), 528- [115]
533.
http://dx.doi.org/10.1021/acsmedchemlett.8b00018 PMID:
29937977
[102] Kramer, C.; Fuchs, J.E.; Whitebread, S.; Gedeck, P.; Liedl, K.R.
Matched molecular pair analysis: Significance and the impact of
experimental uncertainty. J. Med. Chem., 2014, 57(9), 3786-3802.
http://dx.doi.org/10.1021/jm500317a PMID: 24738976
[103] Li, H.; Hou, J.; Adhikari, B.; Lyu, Q.; Cheng, J. Deep learning
methods for protein torsion angle prediction. BMC Bioinformatics,
2017, 18(1), 417.
http://dx.doi.org/10.1186/s12859-017-1834-2 PMID: 28923002
[104] Sahu, A.; Agrawal, R.K.; Pandey, R. Synthesis and systemic toxici-
ty assessment of quinine-triazole scaffold with antiprotozoal poten-
cy. Bioorg. Chem., 2019, 88, 102939.
http://dx.doi.org/10.1016/j.bioorg.2019.102939 PMID: 31028993
[105] Scott, D.E.; Bayly, A.R.; Abell, C.; Skidmore, J. Small molecules, [116]
big targets: Drug discovery faces the protein-protein interaction
challenge. Nat. Rev. Drug Discov., 2016, 15(8), 533-550.
http://dx.doi.org/10.1038/nrd.2016.29 PMID: 27050677
[106] Cukuroglu, E.; Engin, H.B.; Gursoy, A.; Keskin, O. Hot spots in [117]
protein-protein interfaces: Towards drug discovery. Prog. Biophys.
Mol. Biol., 2014, 116(2-3), 165-173.
http://dx.doi.org/10.1016/j.pbiomolbio.2014.06.003 PMID:
24997383 [118]
[107] Szklarczyk, D.; Franceschini, A.; Wyder, S.; Forslund, K.; Heller,
D.; Huerta-Cepas, J.; Simonovic, M.; Roth, A.; Santos, A.; Tsafou,
K.P.; Kuhn, M.; Bork, P.; Jensen, L.J.; von Mering, C. STRING
v10: protein-protein interaction networks, integrated over the tree [119]
of life. Nucleic Acids Res., 2015, 43(Database issue), D447-D452.
http://dx.doi.org/10.1093/nar/gku1003 PMID: 25352553
[108] Labbé, C.M.; Kuenemann, M.A.; Zarzycka, B.; Vriend, G.; Nico-
laes, G.A.F.; Lagorce, D.; Miteva, M.A.; Villoutreix, B.O.; Speran- [120]
dio, O. iPPI-DB: an online database of modulators of protein-
protein interactions. Nucleic Acids Res., 2016, 44(D1), D542-D547.
http://dx.doi.org/10.1093/nar/gkv982 PMID: 26432833
[109] Wang, J.; Luo, C.; Shan, C.; You, Q.; Lu, J.; Elf, S.; Zhou, Y.;
Wen, Y.; Vinkenborg, J.L.; Fan, J.; Kang, H.; Lin, R.; Han, D.;
Xie, Y.; Karpus, J.; Chen, S.; Ouyang, S.; Luan, C.; Zhang, N.; [121]
Ding, H.; Merkx, M.; Liu, H.; Chen, J.; Jiang, H.; He, C. Inhibition
of human copper trafficking by a small molecule significantly at-
tenuates cancer cell proliferation. Nat. Chem., 2015, 7(12), 968-
979. [122]
http://dx.doi.org/10.1038/nchem.2381 PMID: 26587712
[110] Maheshwari, S.; Brylinski, M. Template-based identification of
protein-protein interfaces using eFindSitePPI. Methods, 2016, 93,
64-71.
http://dx.doi.org/10.1016/j.ymeth.2015.07.017 PMID: 26235816 [123]
[111] De Fauw, J.; Ledsam, J.R.; Romera-Paredes, B.; Nikolov, S.; To-
masev, N.; Blackwell, S.; Askham, H.; Glorot, X.; O’Donoghue,
B.; Visentin, D.; van den Driessche, G.; Lakshminarayanan, B.;
Meyer, C.; Mackinder, F.; Bouton, S.; Ayoub, K.; Chopra, R.; [124]
King, D.; Karthikesalingam, A.; Hughes, C.O.; Raine, R.; Hughes,
J.; Sim, D.A.; Egan, C.; Tufail, A.; Montgomery, H.; Hassabis, D.;
Rees, G.; Back, T.; Khaw, P.T.; Suleyman, M.; Cornebise, J.;
Keane, P.A.; Ronneberger, O. Clinically applicable deep learning [125]
for diagnosis and referral in retinal disease. Nat. Med., 2018, 24(9),
1342-1350.
http://dx.doi.org/10.1038/s41591-018-0107-6 PMID: 30104768
Sahu et al.
Yauney, G.; Shah, P. Reinforcement learning with action-derived
rewards for chemotherapy and clinical trial dosing regimen selec-
tion. Proc. 3rd Mach. Learn. Healthc. Conf., 2018, pp. 161-226.
Ohnstad, H.O.; Borgen, E.; Falk, R.S.; Lien, T.G.; Aaserud, M.;
Sveli, M.A.T.; Kyte, J.A.; Kristensen, V.N.; Geitvik, G.A.;
Schlichting, E.; Wist, E.A.; Sørlie, T.; Russnes, H.G.; Naume, B.
Prognostic value of PAM50 and risk of recurrence score in patients
with early-stage breast cancer with long-term follow-up. Breast
Cancer Res., 2017, 19(1), 120.
http://dx.doi.org/10.1186/s13058-017-0911-9 PMID: 29137653
Shimizu, H.; Nakayama, K.I.A. A 23 gene-based molecular prog-
nostic score precisely predicts overall survival of breast cancer pa-
tients. EBioMedicine, 2019, 46, 150-159.
http://dx.doi.org/10.1016/j.ebiom.2019.07.046 PMID: 31358476
Curtis, C.; Shah, S.P.; Chin, S.F.; Turashvili, G.; Rueda, O.M.;
Dunning, M.J.; Speed, D.; Lynch, A.G.; Samarajiwa, S.; Yuan, Y.;
Gräf, S.; Ha, G.; Haffari, G.; Bashashati, A.; Russell, R.; McKin-
ney, S.; Langerød, A.; Green, A.; Provenzano, E.; Wishart, G.;
Pinder, S.; Watson, P.; Markowetz, F.; Murphy, L.; Ellis, I.;
Purushotham, A.; Børresen-Dale, A.L.; Brenton, J.D.; Tavaré, S.;
Caldas, C.; Aparicio, S.; Speers, C.; Watson, P.; Blamey, R.;
Green, A.; MacMillan, D.; Rakha, E.; Gillett, C.; Grigoriadis, A.;
De Rinaldis, E.; Tutt, A.; Parisien, M.; Troup, S.; Chan, D.; Field-
ing, C.; Maia, A.T.; McGuire, S.; Osborne, M.; Sayalero, S.M.;
Spiteri, I.; Hadfield, J.; Bell, L.; Chow, K.; Gale, N.; Kovalik, M.;
Ng, Y.; Prentice, L.; Tavaré, S.; Markowetz, F.; Langerød, A.;
Provenzano, E.; Purushotham, A.; Børresen-Dale, A.L.; Caldas, C.
The genomic and transcriptomic architecture of 2,000 breast tu-
mours reveals novel subgroups. Nature, 2012, 486(7403), 346-352.
http://dx.doi.org/10.1038/nature10983 PMID: 22522925
Merget, B.; Turk, S.; Eid, S.; Rippmann, F.; Fulle, S. Profiling
prediction of kinase inhibitors: Toward the virtual assay. J. Med.
Chem., 2017, 60(1), 474-485.
http://dx.doi.org/10.1021/acs.jmedchem.6b01611 PMID: 27966949
Grys, B.T.; Lo, D.S.; Sahin, N.; Kraus, O.Z.; Morris, Q.; Boone,
C.; Andrews, B.J. Machine learning and computer vision approach-
es for phenotypic profiling. J. Cell Biol., 2017, 216(1), 65-71.
http://dx.doi.org/10.1083/jcb.201610026 PMID: 27940887
Chen, H.; Engkvist, O.; Wang, Y.; Olivecrona, M.; Blaschke, T.
The rise of deep learning in drug discovery. Drug Discov. Today,
2018, 23(6), 1241-1250.
http://dx.doi.org/10.1016/j.drudis.2018.01.039 PMID: 29366762
Choi, E.; Schuetz, A.; Stewart, W.F.; Sun, J. Using recurrent neural
network models for early detection of heart failure onset. J. Am.
Med. Inform. Assoc., 2017, 24(2), 361-370.
http://dx.doi.org/10.1093/jamia/ocw112 PMID: 27521897
Labovitz, D.L.; Shafner, L.; Reyes Gil, M.; Virmani, D.; Hanina,
A. Using artificial intelligence to reduce the risk of nonadherence
in patients on anticoagulation therapy. Stroke, 2017, 48(5), 1416-
1419.
http://dx.doi.org/10.1161/STROKEAHA.116.016281 PMID:
28386037
Macalino, S.J.Y.; Gosu, V.; Hong, S.; Choi, S. Role of computer-
aided drug design in modern drug discovery. Arch. Pharm. Res.,
2015, 38(9), 1686-1701.
http://dx.doi.org/10.1007/s12272-015-0640-5 PMID: 26208641
Li, D.; Chi, B.; Wang, W.W.; Gao, J.M.; Wan, J. Exploring the
possible binding mode of trisubstituted benzimidazoles analogues
in silico for novel drug designtargeting Mtb FtsZ Med. Chem. Res.,
2017, 26, 153-169.
http://dx.doi.org/10.1007/s00044-016-1734-4
Jamal, S.; Khubaib, M.; Gangwar, R.; Grover, S.; Grover, A.;
Hasnain, S.E. Artificial intelligence and machine learning based
prediction of resistant and susceptible mutations in Mycobacterium
tuberculosis. Sci. Rep., 2020, 10, 1-16.
Lind, A.P.; Anderson, P.C. Predicting drug activity against cancer
cells by random forest models based on minimal genomic infor-
mation and chemical properties. PLoS One, 2019, 14(7), e0219774.
http://dx.doi.org/10.1371/journal.pone.0219774 PMID: 31295321
Wang, Y.; Wang, Z.; Xu, J.; Li, J.; Li, S.; Zhang, M.; Yang, D.
Systematic identification of non-coding pharmacogenomic land-
scape in cancer. Nat. Commun., 2018, 9(1), 3192.
http://dx.doi.org/10.1038/s41467-018-05495-9 PMID: 30093685
Artificial Intelligence (AI) in Drugs and Pharmaceuticals Combinatorial Chemistry & High Throughput Screening, 2022, Vol. 25, No. 11
[126] Leventakos, K.; Helgeson, J.; Mansfield, A.S.; Deering, E.;
Schwecke, A.; Adjei, A.; Molina, J.; Hocum, C.; Halfdanarson, T.;
Marks, R.; Parikh, K.; Pomerleau, K.; Coverdill, S.; Rammage, M.;
Haddad, T. Implementation of Artificial Intelligence (AI) for Lung
Cancer Clinical Trial Matching in a Tertiary Cancer Center. Ann.
Oncol., 2019, 30, ii74.
http://dx.doi.org/10.1093/annonc/mdz065
[127] Pantuck, A.J.; Lee, D-K.; Kee, T.; Wang, P.; Lakhotia, S.; Silver-
man, M.H.; Mathis, C.; Drakaki, A.; Belldegrun, A.S.; Ho, C-M.;
Ho, D. Artificial intelligence: Modulating BET bromodomain in-
hibitor ZEN-3694 and enzalutamide combination dosing in a meta-
static prostate cancer patient using CURATE.AI, an artificial intel-
ligence platform (Adv. Therap. 6/2018). Adv. Ther., 2018, 1,
1870020.
http://dx.doi.org/10.1002/adtp.201870020
[128] Gulhan, D.C.; Lee, J.J.K.; Melloni, G.E.M.; Cortés-Ciriano, I.;
Park, P.J. Detecting the mutational signature of homologous re-
combination deficiency in clinical samples. Nat. Genet., 2019,
51(5), 912-919.
http://dx.doi.org/10.1038/s41588-019-0390-2 PMID: 30988514
[129] Goecks, J.; Jalili, V.; Heiser, L.M.; Gray, J.W. How Machine learn-
ing will transform biomedicine. Cell, 2020, 181(1), 92-101.
http://dx.doi.org/10.1016/j.cell.2020.03.022 PMID: 32243801
[130] Watson, O.P.; Cortes-Ciriano, I.; Taylor, A.R.; Watson, J.A. A
decision-theoretic approach to the evaluation of machine learning
algorithms in computational drug discovery. Bioinformatics, 2019,
35(22), 4656-4663.
http://dx.doi.org/10.1093/bioinformatics/btz293 PMID: 31070704
[131] Rutering, J.; Ilmer, M.; Recio, A.; Coleman, M.; Vykoukal, J.; Alt,
E.; Orleans, N. Mutational landscape of metastatic cancer revealed
from prospective clinical sequencing of 10,000 patients. Nat. Med.,
2016, 5, 1-8.
1837
[132] BIO industry analysis. Clinical Development Success Rates 2006-
2015. Bio Ind. Anal. Rep., 2016. Available from:
https://www.bio.org/sites/default/files/Clinical
[133] Abramoff, M.D.; Lavin, P.T.; Birch, M.; Shah, N.; Folk, J.C. Piv-
otal trial of an autonomous AI-based diagnostic system for detec-
tion of diabetic retinopathy in primary care offices. NPJ Digital
Med., 2018, 1, 39.
[134] Chan, B. The rise of artificial intelligence and the crisis of moral
passivity. AI Soc., 2020, 35, 991-993.
http://dx.doi.org/10.1007/s00146-020-00953-9
[135] Fleming, N. How artificial intelligence is changing drug discovery.
Nature, 2018, 557(7707), S55-S57.
http://dx.doi.org/10.1038/d41586-018-05267-x PMID: 29849160
[136] Yu, K.H.; Kohane, I.S. Framing the challenges of artificial intelli-
gence in medicine. BMJ Qual. Saf., 2019, 28(3), 238-241.
http://dx.doi.org/10.1136/bmjqs-2018-008551 PMID: 30291179
[137] Collins, G.S.; Reitsma, J.B.; Altman, D.G.; Moons, K.G.M. Trans-
parent reporting of a multivariable prediction model for individual
prognosis or diagnosis (TRIPOD): The TRIPOD statement. BMJ,
2015, 350, g7594.
http://dx.doi.org/10.1136/bmj.g7594 PMID: 25569120
[138] Ting, D.S.W.; Cheung, C.Y.L.; Lim, G.; Tan, G.S.W.; Quang,
N.D.; Gan, A.; Hamzah, H.; Garcia-Franco, R.; San Yeo, I.Y.; Lee,
S.Y.; Wong, E.Y.M.; Sabanayagam, C.; Baskaran, M.; Ibrahim, F.;
Tan, N.C.; Finkelstein, E.A.; Lamoureux, E.L.; Wong, I.Y.; Bress-
ler, N.M.; Sivaprasad, S.; Varma, R.; Jonas, J.B.; He, M.G.; Cheng,
C.Y.; Cheung, G.C.M.; Aung, T.; Hsu, W.; Lee, M.L.; Wong, T.Y.
Development and validation of a deep learning system for diabetic
retinopathy and related eye diseases using retinal images from mul-
tiethnic populations with diabetes. JAMA, 2017, 318(22), 2211-
2223.
http://dx.doi.org/10.1001/jama.2017.18152 PMID: 29234807