Expert Opinion on Drug Discovery

ISSN: 1746-0441 (Print) 1746-045X (Online) Journal homepage: https://www.tandfonline.com/loi/iedc20

The power of deep learning to ligand-based novel

drug discovery

Igor I. Baskin

To cite this article: Igor I. Baskin (2020): The power of deep learning to ligand-based novel drug
discovery, Expert Opinion on Drug Discovery, DOI: 10.1080/17460441.2020.1745183

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Published online: 31 Mar 2020.

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EXPERT OPINION ON DRUG DISCOVERY
https://doi.org/10.1080/17460441.2020.1745183

PERSPECTIVE

The power of deep learning to ligand-based novel drug discovery

Igor I. Baskina,b
a
Faculty of Physics, M.V. Lomonosov Moscow State University, Moscow, Russia; bButlerov Institute of Chemistry, Kazan Federal University, Kazan,
Russia

ABSTRACT ARTICLE HISTORY

Introduction: Deep discriminative and generative neural-network models are becoming an integral Received 24 December 2019
part of the modern approach to ligand-based novel drug discovery. The variety of different architec- Accepted 17 March 2020
tures of neural networks, the methods of their training, and the procedures of generating new KEYWORDS
molecules require expert knowledge to choose the most suitable approach. Neural networks; deep
Areas covered: Three different approaches to deep learning use in ligand-based drug discovery are learning; drug discovery;
considered: virtual screening, neural generative models, and mutation-based structure generation. generative models; artificial
Several architectures of neural networks for building either discriminative or generative models are intelligence
considered in this paper, including deep multilayer neural networks, different kinds of convolutional
neural networks, recurrent neural networks, and several types of autoencoders. Several kinds of learning
frameworks are also considered, including adversarial learning and reinforcement learning. Different
types of representations for generating molecules, including SMILES, graphs, and several alternative
string representations are also considered.
Expert opinion: Two kinds of problem should be solved in order to make the models built using deep
neural networks, especially generative models, a valuable option in ligand-based drug discovery: the
issue of interpretability and explainability of deep-learning models and the issue of synthetic accessi-
bility of novel compounds designed by deep-learning algorithms.

1. Introduction This review focuses on the opportunities and benefits that

Artificial neural networks have long been at the center of
attention in chemoinformatics and computational medicinal
chemistry [1–4]. In 2012, in a review article on the prospects
of using machine learning methods in chemoinformatics, it was
pointed to a newly emerged area, called deep learning [5], as
a promising methodology that in the future would allow the de
novo design of novel drugs using generative neural network
models [6]. Indeed, after a few years, a sharp rise in interest in
the use of neural networks in drug discovery began, and at
present, we are witnessing an unprecedented pace of develop-
ment of this scientific direction, as can be seen from the
numerous reviews published over the past few years [4,7–23].
Such a rapid development in recent years has become possible
not only due to the accumulation of a large amount of data in
chemistry and pharmacology and a significant increase in com-
puting power thanks to using GPUs. Undoubtedly, the decisive
factor was the tremendous success of using deep learning in
the processing of text, images, voice, playing games, the crea-
tion of autonomous robots and cars, which allowed achieving
human and even superhuman performance and thereby revo-
lutionizing the field of artificial intelligence (AI). The most effec-
tive and universal approaches developed for this purpose were
transferred after appropriate modifications to the field of drug
discovery. This led to the formation of the concept of AI in drug
discovery, which often includes the use of other machine learn-
ing methods [16,18,19,21,24].
deep learning provides for ligand-based novel drug discovery,
both for virtual screening and for the directed generation of new
chemical structures with desired properties using either neural-
network generative models or mutation-based procedures.
2. Ways to use deep learning in ligand-based novel
drug discovery
Deep learning can be used in ligand-based novel drug discovery (i)
during virtual screening of existing libraries of chemical structures
using discriminative models, i.e. the models that discriminate
between active and inactive compounds or predict activity level,
(ii) in the directed generation of new chemical structures with
desired properties using generative models, i.e. the probabilistic
models from which new molecules can be sampled, and (iii) in
mutation-based molecule generation procedures.
2.1. Deep multilayer neural networks (DNNs)
Virtual screening allows a computer to filter predefined
libraries of chemical compounds, discarding compounds with
unfavorable toxicological properties, or keeping compounds
with the necessary spectrum of activities and favorable phar-
macokinetic properties [25–27]. In this case, deep learning is
usually used to create filters based on classification or regres-
sion models that allow predicting biological activity based on

CONTACT Igor I. Baskin igbaskin@gmail.com Faculty of Physics, M.V. Lomonosov Moscow State University, Moscow, Russia
© 2020 Informa UK Limited, trading as Taylor & Francis Group
2 I. I. BASKIN
Article Highlights
● The power of deep learning to ligand-based drug discovery stems
from the ability to create neural-network filters for virtual screening,
to build and run generative neural-network models, and to control
the mutation-based generation of chemical structures with desired
target properties.
● Deep multilayer neural networks combine and transform initial
descriptors to make them more suitable for predicting target
properties.
● Deep convolutional neural networks can derive descriptors directly
from raw descriptions of chemical structures and use them to predict
the target properties of chemical compounds.
● Deep recurrent neural networks can be used to analyze and generate
chemical structures represented as SMILES strings.
● Deep autoencoders produce revertible descriptors from which che-
mical structures can be reconstructed. In conjunction with recurrent
neural networks, this allows for designing chemical compounds with
desired properties.
● Generative models for performing novel drug discovery can be built
using a variety of deep architectures of neural networks in combina-
tion with adversarial and reinforcement learning.
This box summarizes key points contained in the article.
the values of molecular descriptors [9]. For this, multilayer
neural networks are used, consisting of an input layer, each
neuron of which corresponds to a molecular descriptor, an
output layer, each neuron of which corresponds to one of the
simultaneously predicted properties, and one or several layers
of hidden neurons that serve to learn internal representations
of molecules [28], see Figure 1. Such neural networks with
a single hidden layer are called ‘shallow’, while in the presence
of multiple hidden layers such networks are called ‘deep’. All
hidden layers, along with the output layer, in these networks
are ‘dense’, i.e. each neuron from the next layer receives
signals from all neurons of the previous layer. The outputs of
the neurons of the first hidden layer closest to the input layer
can be considered as a new set of descriptors formed by
combining the original molecular descriptors on the hidden
neurons to increase the predictive performance of the net-
work. The outputs of the neurons of each next hidden layer in
a DNN would be formed by combining the descriptors formed
on the previous hidden layer to make them more suitable for
property prediction. So, when moving from the input to the
output layer in a DNN, increasingly higher-level descriptors are
formed on the hidden layers, which are more suitable for
predicting the target property. Thus, a unique feature of
deep learning in DNNs is the gradual nonlinear transformation
of the descriptor description of the molecules, which leads to
Figure 1. A deep multilayer neural network applied to the prediction of three target properties of chemical compounds.
a simpler character of the dependence of the target properties
on them and thereby to a higher predictive ability. This is
fundamentally different from standard machine learning
methods, where the possibility of transforming the descriptor
space of molecules is confined only to descriptor selection and
the formation of their linear combinations (as in the partial
least squares method).
The performance of deep learning in building structure-
activity models useful for drug discovery was compared with
that of other state-of-the-art machine learning methods in sev-
eral benchmark studies, starting from the pioneer publication of
Dahl et al. reporting the participance in Kaggle competition on
Merck molecular activity challenge [29]. Mayr et al. made such
a comparison for toxicity prediction using Tox21 Data Challenge
and demonstrated that it outperformed other machine learning
methods, including naïve Bayes, support vector machines and
random forest [30]. Moreover, they have demonstrated in the
same publication that the above-discussed hierarchy of chemical
features (descriptors, internal representations) is indeed con-
structed in the hidden layers of DNNs. Lenselink et al. [31] and
Mayr et al. [32] made a large-scale comparison of deep learning
with other machine learning methods for drug target prediction
on ChEMBL, and the supremacy of deep learning was demon-
strated. It was even claimed that ‘the predictive performance of
deep learning is in many cases comparable to that of tests
performed in wet labs (i.e., in vitro assays)’ [32].
2.2. Multitask learning
If there are several neurons in the output layer, each of them is
usually responsible for predicting a separate property/activity.
Since building a model for predicting each of them can be
considered as a separate task, the training of such a neural
network is called multitask learning [33]. If several properties
are related to each other, then it can be expected that
a common model that provides their simultaneous prediction
should have a higher predictive performance compared to
individual models due to the ‘inductive transfer of knowledge’
between the tasks. This is achieved through the formation of
common descriptors in hidden neurons. In the field of che-
moinformatics and drug discovery the advantage of perform-
ing multitask learning was first demonstrated by Varnek et al.
on the example of predicting several tissue/air partitioning
coefficients using shallow neural networks [34]. This made it
possible to significantly increase the predictive ability for
models built for human tissues with a small amount of experi-
mental data due to the simultaneous construction of related

models for rodent tissues with a large amount of experimental
data.
The advantage of combining multitask learning with deep
learning is the possibility of forming a deep hierarchy of
general internal representations (descriptors), which provides
more opportunities for ‘induction transfer’ between tasks,
thereby increasing the predictive performance. In one of the
first publications on the use of deep learning in the field of
drug discovery, Ma et al. have applied multitask learning to
build QSAR model and found that the increase in predictive
performance is due to ‘borrowing’ information on related
properties from similar compounds in other datasets [35].
This allowed the authors to develop a strategy for construct-
ing multi-tasking deep neural networks in which cooperation
between different tasks would lead to an improvement in
predictive ability. Recent advances in the use of multitasking
training of deep neural networks in chemoinformatics and
drug discovery have been surveyed by Sosnin et al. [36].
2.3. Convolutional neural networks (CNNs)
The deep multilayer neural networks discussed above use
their hidden layers to transform a fixed number of originally
defined global molecular descriptors into their non-linear
combinations, more suitable for predicting the target proper-
ties of chemical compounds. In this case, global molecular
descriptors are understood as numbers characterizing the
entire chemical structure as a whole and independent of the
numbering of atoms in the molecule, as well as the movement
and rotation of the molecule in space. The success of building
models with such descriptors is largely determined by how
brilliant the scientists who developed such descriptors were
and how successfully a set of descriptors was selected to build
a specific structure-property model. CNNs go much further
and eliminate the subjective human factor by forming global
molecular descriptors directly from a ‘raw’ description of che-
mical structures, such as molecular graphs, see below. In
numerical form, such a ‘raw’ description can be represented
by either a variable or a fixed number of local descriptors (e.g.
indicators of atom types or local charges on atoms), the values
of which depend on the permutations of atoms in the mole-
cules or on the movement and rotation of the molecule in
space. CNNs transform such local descriptors into global ones
using special convolutional and pooling layers of hidden neu-
rons (Figure 2). In contrast to the dense hidden layers consid-
ered above, neurons of a convolutional layer receive signals
only from a small portion of the previous layer, called the
receptor field, by analogy with the mechanism of vision in
Figure 2. A graph convolutional neural network applied to the prediction of three target properties of chemical compounds.
EXPERT OPINION ON DRUG DISCOVERY 3
biology, and the weights of the connections going to them
(called filters, by analogy with image processing) are common
to (shared among) all neurons of the convolutional layer. The
purpose of the convolutional layer is to transform local
descriptors to take into account the influence of the nearest
neighborhood (for example, the influence of the nearest
atoms in a molecule) to increase the predictive performance
of the neural network. The pooling layers consist of neurons
with fixed weights that generalize the local descriptors formed
in the convolutional layers and turn them into a set of a fixed
number of global descriptors. Further, the global molecular
descriptors formed in the last pooling layer can enter the
input of DNN with dense hidden layers. Thus, due to the
automatic formation of local and then global molecular
descriptors in hidden layers, CNNs can build direct correlations
between ‘raw’ descriptions of chemical structures and their
target properties. For the first time, the ability to perform
direct structure-property correlations using similar principles
was demonstrated in the 90 s using ‘a neural device for
searching direct correlations between structures and proper-
ties of chemical compounds’ [37].
There exist several types of CNNs depending on the type of
‘raw’ representation of molecules. The most popular among
them are 1D-, 2D-, 3D-, and graph-CNNs. 1D-CNNs use SMILES
[38] as a ‘raw’ representation and ‘one-hot’ encoding of
a character in each position of the string as initial local
descriptors. A ‘one-hot’ encoded character is a vector contain-
ing 1 in the position corresponding to its type and 0 else-
where. As an example, this kind of network was used by Kwon
and Yoon in the DeepCCL method to predict chemical-
chemical interaction directly from SMILES strings [39]. 2D-
CNNs use graphic images of structural formulas as a ‘raw’
representation of chemical structures and color codes of indi-
vidual pixels as initial local descriptors. So, one can produce
images for the structural formula of all chemical compounds in
the dataset and use powerful image recognition software to
build predictive models for target properties. This methodol-
ogy has been successfully applied in several publications
[40,41] and led to the discovery of CDK4 inhibitors in ligand-
based virtual screening [42]. 3D-CNNs use molecular fields
(both ‘real’ physical fields, such as electrostatic potential, and
pseudo-fields indicating the presence of certain atom types at
given location in fuzzy manner) as a ‘raw’ representation of
chemical structures and the values of such molecular fields
computed for individual voxels (3D analogs of pixels) as initial
local descriptors. Although most of the work on the use of this
type of neural network involves the consideration of protein-
ligand complexes, this network architecture can successfully
4 I. I. BASKIN
be applied to build 3D-QSAR models [43,44]. Graph-CNNs use
molecular graphs as a ‘raw’ representation of chemical struc-
tures, properties of atoms as initial local descriptors, and close
neighborhood of atoms in molecules as ‘receptive fields’ for
neurons in convolutional layers. Currently, deep neural net-
works with such an architecture are actively used to automa-
tically generate global descriptors for predicting various
properties of chemical compounds [45–49]. In addition, graph-
CNNs are currently used as blocks in neural networks with
more complex architectures, including mechanisms that
allow one to focus ‘attention’ on individual molecules or
their parts [50]. In particular, they are part of a special archi-
tecture of neural networks, which allows building classification
models for predicting the type of biological activity in the
presence of a very small number of examples within the
framework of the so-called ‘one-shot learning’ [51], see discus-
sion in Ref [52].
2.4. Recurrent neural networks (RNNs)
RNNs work with molecules represented as sequences, e.g.
sequences of characters in SMILES strings for small molecules
(Figure 3). RNNs iteratively, starting from the first element, apply
the same recurrent procedure to all elements of the sequence,
while forming in its hidden layers descriptors for its first
t elements, dt, by combining already computed descriptors for
the first t-1 elements, dt−1, with initial local descriptors for the t-th
element, it. This is provided by special recurrent neurons, in which
the outputs change with discrete time t, and a special loop with
time delay connects the neuron at time t-1 with itself at time t. In
order to solve some problems associated with the functioning of
RNNs, instead of simple recurrent neurons, it is customary to use
special microarchitectures, particularly LSTM (Long Short-Term
Memory) [53] and GRU (Gated Recurrent Units) [54].
In the case of SMILES, the initial local descriptors for the t-th
element is a ‘one-hot’ encoded type of character at the t-th
position of the string. After passing through the whole SMILES
string a vector of global molecular descriptors is formed for the
corresponding chemical structure. In this case, an RNN can be
trained to predict each t-th character from the descriptors dt−1
computed for the previous substring, using a large set of correct
SMILES. Descriptor vectors computed for the whole SMILES
strings can be used for building models to predict chemical
properties, like in the SMILES2vec approach [55].
The ability of a trained RNN to predict the next character in
a partially formed SMILES can efficiently be used to generate
Figure 3. A recurrent neural network applied to the prediction (in training mode) or the generation (in generator mode) of the SMILES string for ethanol.
new chemical structures. This can be performed because, in
addition to the input and hidden layers in RNNs, there is also
an output layer with the softmax activation function that
calculates the probability of each type for the next symbol.
So, in the generator mode, this probability distribution can be
sampled, and the ‘one-hot encoded’ sampled character can be
used as an input to the network in order to generate one
more character, etc. The growth of the current SMILES string
can be terminated upon the generation of a special stop-
symbol. In this way, new chemical structures that can further
be used in virtual screening can be generated [56]. In order to
direct the neural network to generate structures with desired
properties, several approaches have been developed. One of
them is based on so-called transfer learning in which
a network is first trained on a large data set to generate
correct SMILES and then fine-tuned to specific ligand subsets
to generate active structures for specific biological targets [57].
2.5. Deep reinforcement learning
Another approach to generate structures with desired properties
is to use reinforcement learning (RL), which is a general framework
in machine learning dealing with how software ‘agents’ learn to
take actions in an ‘environment’ so as to maximize reward (or
minimize penalty) [58]. RL is used in AI to solve dynamic decision
problems, so as to take such actions that would lead to desirable
outcome. RL powered by deep neural networks implementing its
functions is called deep RL. In application to the generation of
chemical structures, RL ‘rewards’ for generating structures with
desired target properties and ‘punishes’ for undesired properties,
like in the method of performing de novo design developed by
Popova et al. [59]. In the case of generating SMILES by an RNN,
the network is rewarded during the training whenever
a completely generated SMILES corresponds to a correct chemi-
cal structure possessing desirable properties. So, due to the use
of deep RL, RNNs learn how to produce each next character in
SMILES in order to be able to generate chemical structures with
desired properties. Deep RL is currently very actively used in drug
discovery in conjunction with various approaches to generate
chemical structures [58–64]. Some of them will be considered
below.
2.6. Autoencoders
An autoencoder is a neural network containing two subnetworks,
an encoder and a decoder [28], see Figure 4. The encoder transforms

Figure 4. An autoencoder transforming a chemical structure to a code vector in the autoencoder latent space followed by the reconstruction of the chemical
structure from it.
an initial representation of a molecule to a set of descriptors, called
code vector, from which the decoder reconstructs the initial repre-
sentation. The code vectors form the latent space of the autoenco-
der. The training of the autoencoder is aimed at reducing the
reconstruction error with the smallest possible number of code
descriptors. If such autoencoder is trained using a set of com-
pounds with a certain type of biological activity, then the recon-
struction error can be used as a scoring function in virtual
screening to discover novel drugs belonging to the same activity
class [65,66]. The use of deep learning enables autoencoders to
work with ‘raw’ representations of chemical structures. In particu-
lar, chemical structures represented using SMILES strings can be
processed using a sequence-to-sequence architecture in which
RNNs are used both for encoding the SMILES strings to code
vectors and decoding them back to the SMILES strings [67]. In
this case, the goal of the training is to correctly restore SMILES
strings from their code vectors. Xu et al. have shown that such code
vectors, called ‘seq2seq fingerprints’, could be useful for drug
discovery, because chemical structures can be reconstructed
from them using the decoder [68].
Several approaches to the generation of chemical structures
with desired properties using autoencoder code vectors have
been proposed. All of them are based on (1) approximation of
the statistical distribution of molecules in the latent space
defined by code vectors, (2) sampling of new points from this
distribution, (3) restoration of chemical structures from them
using the decoder. Sattarov et al. approximated molecule dis-
tribution using the GTM (Generative Topographic Mapping)
machine learning method, used the ‘activity landscape’ metho-
dology to select zones enriched with molecules with the desired
activity and generated new molecules by feeding the points
sampled in the latent space from such zones to the decoder [69].
Several published approaches to generation of chemical
structures with desired properties are based on the use of
variational autoencoders (VAE) – a special modification of auto-
encoders in which a molecule is mapped by the encoder not
to a single code vectors but to a Gaussian distribution over the
latent space containing all possible code vectors [70]. During
the training, the decoder learns to reconstruct the original
molecule from a random code vector sampled from this dis-
tribution. Since any point close to the original distribution of
molecules in the latent space can be sampled, VAE creates its
latent space with much fewer ‘holes’ (zones in the latent space
from which correct molecules cannot be reconstructed) in
EXPERT OPINION ON DRUG DISCOVERY 5
comparison with ordinary autoencoders. This allows drawing
continuous trajectories in the latent space, from each point of
which molecules can be reconstructed. This allowed Gomez-
Bombarelli et al. to propose a method for optimizing chemical
structures in order to improve the desired properties [71]. For
this purpose, an additional model can be built to predict the
target properties from the values of latent variables (code
vectors), so optimization of the property in the latent space
results in the optimization of discrete chemical structures. An
important modification of VAEs are conditional VAEs (CVAEs)
where vectors of target properties are injected into the auto-
encoder, so it is possible to generate chemical structures with
a set of desired target properties without the need to perform
optimization in the latent space [72]. Another way to perform
the similar conditional molecular design of compounds with
desired target properties is to use a semi-supervised modifica-
tion of VAEs (SSVAEs) trained on a set of partially annotated
chemical compounds, so new molecules with desired proper-
ties can be generated by sampling from the conditional dis-
tribution without any extra optimization [73].
Zhavoronkov et al. used VAE with a rich prior distribution
in the latent space in combination with tensor decomposi-
tion and RL based on reward functions approximated by
self-organizing maps (SOMs) to discover novel potent inhi-
bitors of discoidin domain receptor 1 in 21 days [74], see
Figure 5.
2.7. Adversarial learning
The disadvantage of VAEs is their tight attachment to the
Gaussian distribution used as a prior, while the distribution
of chemical compounds in databases is often far from
Gaussian and has many modes. Such a mismatch can lead to
the appearance of large ‘holes’ in some zones in the latent
space, which may make it poorly suitable for optimizing che-
mical structures. An effective approach to solving this problem
is to use adversarial learning, which underlies generative adver-
sarial nets (GANs) [75]. GANs consist of two networks,
a generator, which learns to generate new objects, and dis-
criminator, which learns to discriminates between real and
generated objects. The adversarial learning is like a game in
which the generator learns to ‘fool’ the discriminators which
also learns not to be ‘fooled’, and in the result, the generator
becomes so ‘smart’ that the generated objects become
6 I. I. BASKIN

Figure 5. Novel potent inhibitors of human DDR1 kinase found by DL-driven de novo drug design.

indistinguishable from the real ones. Adversarial autoencoders 2.8. Graph-based generation of chemical structures
(AAEs) combine autoencoders with adversarial learning. In this
The above-discussed SMILES-based generation of chemical
case, an additional discriminator neural network learns to
structures has, however, serious limitations. First, the genera-
discriminate between the code vectors produced by the enco-
tor should know or learn from data the grammar of SMILES in
der and random vectors sampled from the user-defined prior
order to keep all parentheses balanced and all ring closures
distribution, while the encoder learns to ‘fool’ the discrimina-
paired. Second, multiple SMILES can be assigned to the same
tor and generate code vectors in accordance with the speci-
chemical structure, while rather dissimilar canonical SMILES
fied prior distribution. For the first time, AAEs were applied by
can correspond to very similar molecules, leading to bad
Kadurin et al. to generate molecular fingerprints, which can
neighborhood behavior [81]. To address these problems, it
further be used for discovering new drugs through virtual
has been suggested to use deep learning algorithms to gen-
screening [76]. Blaschke et al. have applied AAEs for producing
erate chemical structures as molecular graphs directly, without
the latent space for performing optimization of chemical
the use of SMILES. In this case, VAE, GAN and RL frameworks
structures to perform de novo molecular design using the
can be combined with graph-CNNs. Only a few examples from
Bayesian optimization algorithm [77]. They have demonstrated
this fast-growing research domain are given here. Simonovsky
the advantage of using AAEs with the uniform prior distribu-
et al. [82], Jin et al. [81], and Samanta et al. [83] have devel-
tion over the standard VAEs. The above-mentioned Bayesian
oped special graph-based VAEs, whereas De Cao and Kipf [84]
optimization algorithm applied to optimization of molecules
have developed a graph-based GAN. Popova et al. have devel-
works by maximizing the probability of being active against
oped autoregressive MolecularRNN, a graph recurrent genera-
a specific target predicted by Gaussian processes [78] models.
tive model for generating chemical structures with desirable
Such models are first trained with a set of initial points in the
properties, which is trained using RL [85].
autoencoder latent space, then in each iteration a new point
A common drawback of graph-based methods for generating
selected by maximizing a certain probabilistic criterion based
chemical structures is significantly lower computational effi-
on the current model is added to the set, the model is rebuilt
ciency and significantly greater memory requirements compared
and so on. Prykhodko et al. have developed the LatentGAN
to the SMILES-based methods. This, in turn, imposes certain
architecture which also combines an autoencoder with a GAN
restrictions on the size of molecular graphs. An effective solution
for de novo molecular design [79]. Guimaraes et al. have
to this and several other problems has recently been proposed
combined SMILES-based structure generation with both the
using a very promising approach – graph normalizing flows.
adversarial and RL into the ORGAN (Objective-Reinforced
A normalizing flow is a transformation of a simple probability
GANs) network, in which the generator is trained to maximize
distribution (like a Gaussian distribution in a latent space) into
two rewards, the first one that improves the activity of mole-
a probability distribution of any complexity (like distribution of
cules, and the second one that learns to mimic real molecules
molecules in chemical space) by a sequence of invertible and
by ‘fooling’ the discriminator [80].
differentiable mappings [86,87]. Unlike VAEs and GANs, they can

approximate data distributions exactly and provide from them
sampling very efficiently due to the invertibility of transforma-
tions. Since normalizing flows can operate both in continuous
and discrete domains, they have been adopted to generate
graphs. This has recently led to the development of three novel
methods for generating molecular graphs: GraphNVP [88],
GRevNets [89] and GraphAF [90].
2.9. Generation of chemical structures using alternative
string representations
Despite the above issues, using SMILES to generate chemical
structures, however, has some clear advantages, including
simplicity, versatility, and the ability to use a rich arsenal of
methodologies and software tools designed for text mining.
Several approaches were proposed to overcome the draw-
backs of using SMILES, while still preserving the benefits of
using strings. First, it has been shown that the problem of
poor neighborhood behavior for canonical SMILES can be
overcome by using sets of different non-canonical SMILES
strings [91]. Second, several alternative string representations
addressing the grammar-related problem have been sug-
gested. Kusner et al. have developed the GrammarVAE
approach based on representing SMILES as a grammar parse
tree, so all SMILES stings generated using VAEs (see above) are
guaranteed to have valid syntax [92]. To achieve the same
goal, O’Boyle and Dalke have developed DeepSMILES,
a modification of SMILES which avoids the problems of unba-
lanced parentheses and pairing ring closure symbols [93].
Krenn et al. have developed the SELFIES string representation
based on a Chomsky type-2 grammar that can be used to
represent graphs so that random modifications in them would
lead to correct semantically-constrained graphs [94].
2.10. Mutation-based generation of chemical structures
A reasonable alternative to the neural-network generation of
new chemical structures in de novo drug design is a more
traditional approach, which consists in modifying molecules
using chemical ‘mutations’. In the past year, there has been
a trend in combining nutation-based structure generation
with deep learning. For example, Zhou et al. have combined
optimization of molecules using a small set of chemical ‘muta-
tions’ with deep RL in order to generate new molecules with
desired properties [64]. Nigam et al. have combined the
genetic algorithm (GA) based on mutations defined on
SELFIES strings [94] with a DNN-based discriminator model
and have shown that this approach ‘outperforms other gen-
erative models in optimization tasks’ [95].
2.11. Benchmarking generation of chemical structures
In order to compare different generative models for de novo
molecular design, two benchmarking platforms have been devel-
oped, GuacaMol by Brown et al. [96] and MOSES (Molecular SEtS)
by Polykovskiy et al. [97]. Both contain standard molecular bench-
mark datasets, implementations of several algorithms for produ-
cing generative models and generating chemical structures, and
several metrics for comparing the performance of different
EXPERT OPINION ON DRUG DISCOVERY 7
generative models in terms of diversity, different kinds of similarity,
Fréchet ChemNet Distance [98], synthetic accessibility, drug-
likeness, etc.
3. Conclusions
Deep learning provides very powerful tools that can be used
in ligand-based novel drug discovery both to conduct virtual
screening of the already prepared libraries of chemical com-
pounds and to generate new compounds with desired proper-
ties. The deep architecture of neural networks with multiple
hidden layers makes an internal representation of molecules
more suitable for predicting target properties, as well as for
transferring knowledge between different tasks. CNNs can
work directly with chemical structures without the use of
descriptor sets previously invented by humans. Using RNNs,
one can apply text processing methods to chemical structures
represented using SMILES strings. Chemical structures can be
generated either through SMILES strings or directly working
with molecular graphs. Autoencoders can be used to produce
‘invertible’ descriptors from which chemical structures can be
recovered. This allows one to effectively design new com-
pounds, both by generating new chemical structures for
a given property and by optimizing chemical structures in
the latent space of autoencoders. Different types of VAEs,
GANs, and RL are powerful tools that can be very useful for
ligand-based drug discovery. Several success stories that have
already been reported in the literature.
4. Expert opinion
Despite very promising results obtained by using deep learn-
ing in ligand-based drug discovery, it is necessary to note
some still challenging problems. The first one is the issue of
interpretability, explainability, and integration with deep
scientific knowledge. The discovery of drugs is a very long
and expensive process, in which many specialists from various
fields are involved, who should well understand the decisions
made by colleagues. The process of drug design powered by
AI-based on deep learning algorithms should not be per-
ceived as a sort of magic that can only be blindly believed
but not completely trusted. Unfortunately, this is not facili-
tated by the ‘black box’ nature of deep neural networks,
whose work is still not fully understood by mathematicians
and even their creators. In the field of drug discovery, the
human-AI interaction is very important, and the abbreviation
AI should mean augmented intelligence rather than artificial
intelligence. So, AI should be rather a partner of medicinal
chemists than their replacement. The interpretation of the
neural network model allows a better understanding of the
nature of the phenomenon described by it [99]. Interactive
visualization tools, like those based on GTM landscapes, are
useful for involving humans in the generation of chemical
structures by neural networks [69]. A positive trend is the
explicit consideration of their spatial structure in 3D space in
the process of generating molecules because this is an impor-
tant factor determining the biological activity of drugs [100–
103]. Empowering a neural network with the ability to cor-
rectly consider the fundamental relationships between
8 I. I. BASKIN
different target properties [104], as well as the correct sym-
metry properties [103,105], is also important for taking into
account the laws of the physical world.
Another very important challenging problem is the synthetic
accessibility of chemical compounds in de novo drug design. Ertl
and Schuffenhauer have developed a synthetic accessibility score
based on molecular complexity and fragment contributions [106],
and it is a common practice to use it as one of the objectives in the
process of chemical structure generation and optimization. Coley
et al. have developed for the same purpose a synthetic complexity
score, SCScore, learned from a huge chemical reaction database
[107]. Although the use of such scores leads to the effective rejec-
tion of difficult to synthesize compounds, this problem cannot be
solved without a detailed retrosynthetic analysis with an exact
indication of the structures of the reactants and reagents, along
with the conditions (the temperature, solvent, catalysts, etc.) and
experimental procedure for each of the stages of the synthesis. The
task of planning and conducting organic synthesis is usually the
responsibility of a synthetic chemist, which is not acceptable when
working with a large number of compounds, as well as when
conducting synthesis using autonomous robotic synthetic devices.
It is important to note that in recent years, AI methods based on
deep learning have also taken a decisive role in computer planning
of organic synthesis [108–111], so there is a fundamental possibility
of embedding retrosynthetic analysis in the generation of chemical
structures with desired properties. The first example of the imple-
mentation of such an approach that allows for the generation of
synthetically accessible molecules along with a complete specifi-
cation of their synthesis is the DINGOS system recently developed
by Button et al. [112], which combines the ligand-similarity-based
generation of chemical structures with a machine learning model
trained on successful synthetic roots.
Funding
I Baskin is funded by the Ministry of Education, Youth and Sports of the
Czech Republic (agreement MSMT-5727/2018-2) and the Ministry of
Higher Education and Science of the Russian Federation (project number:
RFMEFI58718X0049).
Declaration of Interest
The authors have no other relevant affiliations or financial involvement
with any organization or entity with a financial interest in or financial
conflict with the subject matter or materials discussed in the manuscript
apart from those disclosed.
Reviewer Disclosures
Peer reviewers on this manuscript have no relevant financial or other
relationships to disclose.
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