CHAPTER 1

Introduction to Artificial Neural

Network (ANN) as a Predictive
Tool for Drug Design, Discovery,
Delivery, and Disposition: Basic
Concepts and Modeling
Munish Puri1, Aum Solanki2, Timothy Padawer2, Srinivas M. Tipparaju2,
Wilfrido Alejandro Moreno3, Yashwant Pathak4
1
Visiting Fellow, National Cancer Institute, NIH, Bethesda, MD, USA; 2Department
of Pharmaceutical Sciences, College of Pharmacy, University of South Florida, Tampa, FL, USA;
3
Department of Electrical Engineering, University of South Florida, Tampa, FL, USA; and R&D
of Ibero-American Science and Technology Education Consortium (ISTEC); 4USF College
of Pharmacy, University of South Florida, Tampa, FL, USA

1. ARTIFICIAL NEURAL NETWORK CONTENTS

An Artificial Neural Network (ANN) is a computational model inspired by net-
1. Artificial Neural
works of biological neurons, wherein the neurons compute output values from Network ............ 3
inputs. All signals can be assigned binary values as either 1 or
1. The neuron
calculates a weighted sum of inputs and compares it to a threshold of 0. If the 2. ANN as a
Classifier........... 5
calculated sum is higher than the threshold, the output is set to 1 or to
1. The
power of the neuron results from its collective behavior in a network where all 3. ANNs in Drug
neurons are interconnected. The network starts evolving: neurons continuously Delivery and
Disposition ........ 6
evaluate their output by looking at their inputs, calculating the weighted sum,
and then comparing to a threshold to decide if they should fire. This is a highly 4. Applications of
complex parallel process whose features cannot be reduced to phenomena ANN Modeling in
Drug Delivery
taking place with individual neurons. One observation is that the evolution and
of an ANN causes it to eventually reach a state where all neurons continue Pharmaceutical
working, but no further changes in their state occur. A network may have Research........... 7
more than one stable state, and it is determined by the choice of synaptic 5. ANN Applications
weights and thresholds for the neurons. in Analytical
Data Analysis and
ANN is a computational model that is based on a machine learning technique.
Structure
It works like a human brain neuron system. This machine learning technique Retention
follows the same pattern of learning, that is, learning from its past experience 3
Artificial Neural Network for Drug Design, Delivery and Disposition. http://dx.doi.org/10.1016/B978-0-12-801559-9.00001-6
Copyright © 2016 Elsevier Inc. All rights reserved.
4 CHAPTER 1: Introduction to Artificial Neural Network (ANN)

Relationship and mistakes like mammalian neurons to achieve the target value. An algo-
Methodology ..... 7 rithm is designed on the basis of a neural network system to implement a par-
6. ANN allel computational power of neurons. ANN learns from its past experience and
Application in errors in a nonlinear parallel processing manner using a popular algorithm
Preformulation named “feed forward and backpropagation.” The term “feed forward” describes
and Optimization how the neural network processes and recalls patterns. In a feed forward neural
of
Pharmaceutical network, neurons are only connected forward. Each layer of the neural network
Formulation...... 8 contains connections to the next layer, but there are no connections back. The
term “backpropagation” describes how this type of neural network is trained.
7. In Vitro In Vivo
Backpropagation is a form of supervised training. When using a supervised
Correlation ....... 9
training method, the network must be provided with both sample inputs
8. ANN Applications and anticipated outputs. The anticipated outputs are compared against the
in Predicting
actual outputs for given input. Using the anticipated outputs, the backpropaga-
BloodeBrain
Barrier tion training algorithm takes a calculated error and adjusts the weights of the
Permeability ... 10 various layers backward from the output layer to the input layer to reduce
the value of error. The information is delivered to output if it achieves the
9. Quantitative
Structure- target; otherwise, it is backpropagated. Hence the name of the algorithm is
Activity feed forward backpropagation. The target value will only be achieved if the
Relationships weighted sum will meet the minimum threshold and hence feed forward or
(QSAR) and backpropagate for further processing. ANN could be an excellent choice to pro-
Quantitative cess large biological data for a more accurate prognosis. The prognostic tools
Structure-
Property can be designed based on ANN’s powerful learning and processing characteris-
Relationships tics, which can work perfectly even in a highly probabilistic and noisy environ-
(QSPR)............. 11 ment. The power of the neuron results from its collective behavior in a network
where all neurons are interconnected. The network starts evolving; neurons
continuously evaluate their output by looking at their inputs, calculating the
weighted sum, and then comparing to a threshold to decide if they should fire.
The neuron is the basic calculating entity in ANN processing, which accepts in-
formation from a number of inputs and delivers one output by comparing with
a threshold value. The computational processing is accomplished by internal
structural arrangements that consist of hidden layers and algorithms to deliver
a specified output. The learning is based on reinforcement (supervised) and un-
supervised (no target) types. The unsupervised mimics the biological neuron
pattern of learning.
Basically, ANN is a mathematical model that is used to implement the designed
algorithm-based machine learning techniques. ANN communication is per-
formed by calculating the weights of neural inputs, which works on the basis
of mathematical operations such as multiplication and addition. Each input
received at a nodal point is multiplied with its weights and summed together
before activation (firing). In the case of a biological neuron, the information is
received at dendrites, processed at soma (cell body), and delivered to axon
(output). Similarly, in ANN, the artificial neuron is the basic unit of information
reception where the inputs are received and multiplied, summed, and processed
 2. ANN as a Classifier 5

via a transfer function before being delivered to the output. An ANN model is
so simple and natural that it can handle very complex real-life problems in a
nonparallel and distributive way like a biological neural network. The mathe-
matical description of ANN can be understood by the following equation:
!
Xn
YðtÞ ¼ F ðXiðtÞWiðtÞþ cÞ (1)
i¼1

where
Xi(t) is the input value at time t,
Wi(t) is the weight of neural input at time t,
c is the bias,
F is a transfer function,
Y(t) is the output value at time t.
Note that the transfer function F is to be selected on the basis of the nature of
the problem. It mathematically defines the properties of neurons. It can be any
step function or nonlinear sigmoid function, depending on the problem. The
step function is used to handle classification problems like classifying the
benign and malignant state of breast tumors. Similar to a human neuron
network, ANN should be trained before it is actually applied to a specific prob-
lem. This learning can be supervised or unsupervised in nature.

2. ANN AS A CLASSIFIER
ANN can be used to classify the complex and noisy biological data for prog-
nosis. For example, in breast cancer tumor data, an ANN classifier can be
trained to classify the benign and malignancy states based on descriptors like
cell uniformity, clump thickness, size, shape, intensity, mitosis, etc. Its perfor-
mance is then judged through mean square error and confusion matrices. Data
are loaded in terms of feature elements.
The data available for processing under ANN are distributed in categories such
as training, validation, and testing. Training data are the actual data offered to
a network during training and adjusted according to errors and mistakes.
Validation data are used to test the network performance directly and stop
the processing in case of overfitting. Out of sample testing is an independent
operation and has no effect on ANN operation during training. The hidden
neuron number can be adjusted at any level if the performance is
unsatisfactory.
For example, in the case of breast cancer histopathology image analysis, the
process of classifier design and testing starts with data collection. The high-
resolution cancer images are processed for segmentation using various mathe-
matical models and algorithms. Segmentation techniques like adaptive
6 CHAPTER 1: Introduction to Artificial Neural Network (ANN)

thresholding, water shedding, nearest neighbor, etc. are mainly used before
feeding data to a specific classifier. Pleomorphic (distorted shapes and sizes)
nuclei are then processed for feature extraction like size, shape, textures, etc. un-
der a selective morphometric parameter check. Extracted features are classified
under the neural network algorithm. For next generation healthcare solutions,
ANN computational processing algorithms could be a powerful tool to assist
pathologists in second opinions, efficient drug design, and delivery in the phar-
macy industry in an environment of rapid decision making, reducing the drug
discovery time from lab to market.

3. ANNs IN DRUG DELIVERY AND DISPOSITION

The focus of this chapter is to discuss how ANNs can be applied to drug delivery
and disposition. ANNs provide a virtual method to predict the effects the drug
will have on the body, with the ultimate goal of improving patient care by
streamlining the development of pharmaceuticals. The development of
ANNs in drug disposition is an interdisciplinary and complex area, involving
pharmacologists and computational biologists. The power of ANNs is that
they can minimize the need for traditional pharmacology, including animal
studies, therefore reducing time and costs for drug discovery and develop-
mental research. Software can be used to not only develop new drugs but
also improve current products. However, the precision of ANNs in drug dispo-
sition is still under development, and newer research and tools are evolving. It
is hoped that this area of research will grow along with high throughput tech-
nologies capable of generating “omics” data. The use of biological data gained
in this postgenomic era has opened up a new field referred to as “systems phar-
macology.” A large variety of biological databases exist and offer researchers ac-
cess to a wide range of information, including genomic, proteomic,
metabolomics, drugeprotein interactions, and gene expression. It is possible
that these datasets can be utilized as input for ANNs for answering various
questions in pharmacology [1].
Pharmaceutical therapies take many forms, that is, tablets, liquids, and creams.
These compounds are intended to reach a specific target in order to have the
desired treatment effect. In designing ANNs for drug disposition, the physio-
chemical properties of the active pharmaceutical ingredients (API) and excipi-
ents are of primary importance, along with the processes they undergo in order
to reach their targets [2]. For example, the efficacy of an orally administered
drug will depend on its ability to be efficiently absorbed by the gastrointestinal
(GI) tract. Traditional in vitro dissolution tests face difficulties in accurately pre-
dicting the physiological conditions of the upper GI. The conditions of the GI
are also dynamic and can vary greatly between fasted and fed states. The
differences in these conditions can have a wide effect on drug disposition [3].
 5. ANN Applications in Analytical Data Analysis and Structure Retention Relationship Methodology 7

ANNs for use in drug transport simulation are constructed to best represent the
anatomical system at each step of the absorption process. This type of modeling
simplifies the complex nature in which compounds interact with the body,
starting at the target site of ingestion or application to the therapeutic site.
The ability for the drug to reach specific compartments of the body must be
considered when modeling drug delivery. There are a number of software pack-
ages available that simulate drug transport in the gastrointestinal tract, such as
IntellipharmÔ, GastroPlusÔ, and PK-SimÒ. The section on drug disposition
consists of chapters dealing with this area and further discusses the state of
the art in the field with examples of various therapies. Specific examples include
challenges faced with advanced drug delivery and disposition to specialized
targets, such as ocular drug delivery and transportation, to solid oral tablet
drug transport for hypercholesterolemia treatment. It gives insights into how
ANNs can be used to model each type of therapy.

4. APPLICATIONS OF ANN MODELING IN DRUG

DELIVERY AND PHARMACEUTICAL RESEARCH
The modeling and nonlinear pattern recognition abilities of ANNs increase
their potential applications in many different pharmaceutical research studies.
These applications include drug modeling, pharmacokinetic and pharmacody-
namics modeling, interpretation of analytical data, and, especially, in vitro/
in vivo correlations. Also, ANNs have been used in the field of biopharmaceu-
tical production. Takahashi et al. developed an ANN model to predict molec-
ular and viable cell concentrations based on previously published
UVevisible spectral data [4]. They were able to develop a suitable 4-layered
model that can allow researchers to use UVevisible spectroscopy in order to
characterize cell culture broths instead of using more expensive experimental
techniques [4].

5. ANN APPLICATIONS IN ANALYTICAL DATA

ANALYSIS AND STRUCTURE RETENTION
RELATIONSHIP METHODOLOGY
ANNs can be very useful in predicting the relationship between the structural
properties of a molecule and its behavior in biological and chromatographic
environments. These Structure Retention Relationship (SRRs) can be used to
predict retention for a new solute, identify the most significant structural de-
scriptors of molecules, gain insight into the molecular mechanism of chro-
matographic separation, evaluate physiochemical properties of molecules,
and predict biological activities within a set of drugs and other xenobiotics
[5]. Tham et al. used ANNs to predict the retention capabilities of 18 amino
8 CHAPTER 1: Introduction to Artificial Neural Network (ANN)

acids in reversed-phase, high-performance liquid chromatography (HPLC) [6].

After encoding the amino acids with 36 molecular descriptors, the genetic neural
network method was used to establish the correlation between the molecular
descriptors and retention time. Through a genetic algorithm, it was determined
that a 5-2-1 architecture was the best suited for predicting retention, which
revealed that there is a strong link between the structure of amino acids and
chromatographic separation [6].
D’Archivio et al. used ANNs’ applications in SRR studies to create a model pre-
dicting the Kováts retention indices (RI) of 90 different esters, separated into
seven different groups (columns) based on their polarity [7]. Here again,
ANNs showed their proficiency in nonlinear prediction. The performance of
the ANN model was compared to that of a multiple linear regression (MLR)
model. Both models predicted cross-column RI values comparably. However,
when less similar columns were used, the nonlinear ANN model held a definite
advantage, showing its ability to be applied to a wider range of data [7].
Such applications for SRR studies can be conducted on different natural prod-
ucts as well. HPLC, working in combination with high-resolution mass spec-
troscopy, is generally used to separate natural extracts. Eugster et al.
developed an ANN model using a chemical dataset of 260 different natural
products [8]. They found that an 8-5-1 architecture was the best-suited model
in terms of predictive ability [8]. This predictive ability of the ANN model was
compared to that of partial least square (PLS) regressions. PLS regressions
required the use of multiple models that operated only on certain subsets of
the 260 natural products, whereas the ANN model was able to operate with
comparable predictive ability on the entire set of natural products, again
showing the versatility of ANN models [8].

6. ANN APPLICATION IN PREFORMULATION AND

OPTIMIZATION OF PHARMACEUTICAL
FORMULATION
ANNs can be a useful tool for preformulation studies, as they can be used to
predict the chemical properties of different compounds. Ebube et al. used
ANNs to predict physiochemical properties of amorphous polymers [9]. The
model was able to accurately predict (error of 0e8%) the relationships between
chemical composition of the polymer and the water uptake profiles, viscosity,
and glass transition temperatures [9]. These results show the potential that the
ANN model has as a preformulation tool.
The nonlinear pattern recognition abilities of ANN models can also be incred-
ibly useful in the optimization of pharmaceutical formulations and dosage
methods. ANNs have been shown to be capable predictors of formulations’
 7. In Vitro In Vivo Correlation 9

in vivo dissolution time profiles and bioavailability profiles, making it possible

to identify formulations with such desired characteristics [10]. Subramanian
et al. compared the optimization ability of ANNs to that of MLR analyses
[11]. An ANN model and 33 factorial design model were used to optimize
the formulation parameters of cytarabine liposomes. A set of input variables
was used with 11 hidden layers and one output variable (percentage drug
entrapment). Optimal drug entrapment was found to occur in a 1:13 drug-
to-lipid ratio. The optimization was then validated by preparing additional for-
mulations, revealing that the ANN model provides more accurate predictions
[11]. Kumar et al. used ANNs to optimize fatty alcohol concentration in oil/
water emulsions [12]. An R2 value of 0.84 shows that the ANN model was
successful in predicting the optimal concentration. In order to optimize the
polydispersity index of acetaminophen nanosuspensions, Aghajani et al.
used an ANN model with independent variables: surfactant concentration,
solvent temperature, and flow rate of solvent and antisolvent [13]. Using the
model, it was determined that low polydispersity index (PDI) can be obtained
with high antisolvent flow rates and solvent temperatures and low solvent
flow rates. ANNs have also shown potential as optimization tools for time-
dependent pharmaceutical formulations [14].

7. IN VITRO IN VIVO CORRELATION

The most promising use of the ANN model is, perhaps, its ability to predict
in vivo correlations from in vitro results. Here again, it is the nonlinear
modeling ability of the ANN model that separates it from other regression
methods. Dowell et al. studied the ability of different ANN models as in
vitro in vivo correlation (IVIVC) tools. For simpler sets of data, the feed
forward neural network (FFNN) and the generalized regression neural
network (GRNN) were the best because of their broad predictive ability,
whereas for more complex datasets, it may be necessary to use other types
of neural networks such as jump connection neural networks or recurrent
neural networks [15]. Regardless, ANNs show a great applicability for IVIVCs
because they avoid the need to provide a priori regression equations while
having great predictive ability for complex, multivariable relationships [15].
Parojcic et al. compared the ability of the GRNN model to that of deconvolu-
tion and convolution approaches in predicting IVIVC for the drug release of
paracetamol matrix tablets [16]. Findings showed that the GRNN model was
superior to both approaches, resulting in a better IVIVC in a model that is
easier to use for further research [16].
IVIVC for orally inhaled drugs is difficult to obtain, as there are more variables
affecting the drug’s efficacy, such as lung deposition and total systemic
bioavailability, making ANNs great candidates as possible solutions [17].
10 CHAPTER 1: Introduction to Artificial Neural Network (ANN)

De Matas et al. developed an ANN model that predicted the in vivo efficacy of
dry powder inhaler formulations through the use of in vitro data and param-
eters based on the physiological characteristics of human volunteers [17].
Results showed that the ANN model is a very effective IVIVC tool for inhaled
drugs (R2 z 80%), even though many improvements to the model can be
made through the addition of significant input variables, larger datasets,
and greater numbers of subjects [17]. A similar study developed an IVIVC
for mild/moderate asthmatics receiving monodisperse salbutamol sulfate
aerosols, with seven input variables and one hidden layer [18]. Here again,
the ANN model showed its ability to be an effective predictive tool with results
revealing the significance that aerodynamic particle size has on patient bron-
chodilator responses [18]. ANN models have also shown the ability to develop
IVIVC for self-emulsifying delivery systems, dissolution kinetics in the GI tract,
and metabolic clearance for new drugs [19e21].
The reason IVIVCs are so desirable for pharmaceutical research is that they pro-
vide preliminary information regarding the drug’s in vivo behavior without
conducting extensive in vivo experiments. Mendyk et al. developed a general
IVIVC model that can be used as a preliminary predictor for the in vivo
behavior for various pharmaceutical formulations through the use of detailed
knowledge about their chemical and physiological characteristics [22]. This
model has the potential to be used as a preliminary tool for researchers to study
the bioavailability of new drug formulations.

8. ANN APPLICATIONS IN PREDICTING

BLOODeBRAIN BARRIER PERMEABILITY
In order to be therapeutically effective, many drugs targeted to the brain must
cross the bloodebrain barrier (BBB). It is a selectively permeable physical
barrier composed of endothelial cells, astrocytes, and pericytes [23]. The devel-
opment of a drug delivery system that allows for the sustained release of a drug
to brain tissue is greatly desired. Such delivery systems are being studied
through many in vitro and in vivo methods, but in silico prediction systems
show great promise as preliminary tools. Here is where ANN models show great
promise because of their multivariable pattern recognition abilities. To study
the effects of molecular descriptors on BBB permeability, Garg et al. developed
an ANN model that determined that molecular weight and the topological
polar surface area are the most significant factors that affect a drug’s ability to
cross the BBB [24]. In a similar study, Chen et al. used an 8-5-1 architecture
FFNN model with eight molecular descriptors as the input variables and logBB
as the output variable [25]. This model did not use molecular weight as one of
its input variables, but results from this model highlighted the polar surface
area as a very important factor in determining BBB permeability.
 References 11

9. QUANTITATIVE STRUCTURE-ACTIVITY
RELATIONSHIPS (QSAR) AND QUANTITATIVE
STRUCTURE-PROPERTY RELATIONSHIPS (QSPR)
Quantitative structureeactivity relationships/quantitative structureeproperty
relationships (QSARs/QSPRs) are mathematical models of the relationship
between a drug’s structural properties and its biological behavior [26]. These
relationships can be very complex, which makes the ANN approach an ideal
candidate for QSAR development. In the past, the comparative molecular field
analysis (CoMFA) was widely applied, but the nonlinear pattern recognition
ability of ANNs was recognized to be better suited in developing these
mathematical relationships [27]. In studying retention time behavior for
certain pesticides, it was found that the ANN approach for developing
the QSPR was more effective than an MLR approach with the ANN model
having a mean relative error of 9.04% and the MLR model having an error
of 13.8% [28].
ANN’s predictive ability has also been compared to that of PLS analysis. Vuci-
cevic et al. developed QSPRs for the activity of a2-adrenoreceptors and imida-
zoline receptors in BBB permeability using PLS, MLR, and ANN modeling [29].
Optimal QSPRs were developed for each of these models, and the ANN QSPR
model was found to be the most statistically relevant.
These studies are examples of how ANNs’ nonlinear modeling ability separates
them from other computational models. This modeling ability makes them
ideal candidates as preliminary predictive tools for drug behavior.

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