REVIEWS Drug Discovery Today  Volume 21, Number 8  August 2016

a better understanding of the data in machine learning. Descriptor the basic definition of these descriptors. Mathematical represen-
selection is an important step for several reasons [10], including: (i) tation of these descriptors has to be invariant to the size of the
using only a few descriptors increases the interpretability and molecule and the number of atoms it contains to enable model
understanding of resulting models; (ii) It can reduce the risk of building with statistical methods. Molecular descriptors have
overfitting from noisy redundant molecular descriptors; (iii) it can become the most significant features used in QSAR/QSPR model-
provide faster and cost-effective models; and (4) it removes the ing. The information encoded by descriptors generally depends on
activity cliff. However, noisy, redundant, or irrelevant descriptors the kind of molecular representation and the defined algorithm for
should be removed in a way that the dimension of the input space its calculation. Some of these include: topological indices, and
Reviews  INFORMATICS

is reduced without any loss of significant information [3]. In this
review, we provide an update on, and a brief explanation of,
commonly used descriptors, with a particular emphasis on their
selection approaches for the development of more reliable, pre-
dictable, and generalized QSAR models.
Molecular descriptors
Despite great advances in the field of drug design, the use of
descriptors to define the molecular structure of biologically active
compounds is the main method utilized to discover new lead
molecules. Descriptors are the chemical characteristic of a mole-
cule in numerical form, used for QSAR/QSPR studies. Fig. 1 depicts
geometrical, constitutional and physicochemical descriptors.
Constitutional descriptors are simple, commonly used descriptors
reflecting the molecular composition of a compound without any
information about its topology. The most common constitution
descriptors are number of atoms, bond count, atom type, ring
count, and molecular weight (MW). These descriptors are inert to
any conformation change and, thus, do not distinguish among
isomers.
Topological and geometrical descriptors
Recent advances in strategies of lead discovery, drug designing,
virtual screening, combinatorial library design, and discrimination

Ge
al
om
c et
gi ri
l oBased on molecular graphs Calculated from the 3D c
o

Represents the connectivity coordinates of the atoms.

a
p

Capture the 3D information

l
of atoms in molecules.
To

Used for modeling biological regarding the molecular size,

physicochemical and shape, and atoms distribution.
pharmacokinetic properties. e.g., WHIM, MoRSE and
e.g., Wiener, Zagreb GETAWAY, etc.
connectivity indices, etc.
Thermod
l
tiona

Simple and commonly Thermodynamics descriptors

used descriptors reflecting are used to relate chemical
the chemical information structure to observed
of a molecule without any chemical behavior.
information of atom e.g HF (head of formation),
connectivity.
u

molRef(Molar refractivity)
y

e.g Atom and bond AlogP. etc.

tit

counts, MW. etc. Used to describe

am

electronic aspects of the

s

molecule or atoms bonds

n

ic

and moleculer fragments.

o

e.g Dipolemoment, HOMO, LUMO

C

energy, etc.

Electronic

Drug Discovery Today

FIGURE 1
Representation of molecular descriptors used in quantitative structure–activity relation (QSAR) modeling.

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Drug Discovery Today  Volume 21, Number 8  August 2016
between database searching emphasize the role of topological
descriptors in drug discovery. Topological indices (TIs) are 2D
descriptors that consider the internal atomic arrangement of com-
pounds [11]. They are derived from the topological representation
of molecules and can be considered as structure-explicit descriptors.
These indices encode information about molecular size, shape,
branching, presence of heteroatoms, and multiple bonds in nu-
merical form. These TIs represent the connectivity of atoms in the
molecules by the nature of chemical bonds. They have a significant
role in the modeling of different physicochemical properties, bio-
logical activities, and pharmacokinetic properties. A topological
representation of molecule is presented as a molecular graph. In
mathematical terms, this graph is denoted as G = (V,E), where V is a
set of vertices that correspond to the molecule atoms and E is a set of
elements representing the binary relationship between pairs of
vertices. These chemical graphs represent a non-numeric form of
the molecular structure; however, numerical translation of graph is
essential for the calculation of topological descriptors [12]. A variety
of descriptors are available, among which the most commonly used
are the Wiener index [13], Connectivity indices [14], Kier shape
[15], Balaban J index [16], and Zagreb indices [17]. The main
applications of these indices are to differentiate molecules based
on their size, degree of branching, flexibility, and overall shape. The
Wiener index (W) is the oldest molecular graph-based structure-
descriptor and has become one of the most frequently used descrip-
tors in QSAR/QSPR studies [13]. Among the Tis, the most successful
descriptors are so-called ‘connective indices’. These descriptors are
based on graph-theoretical invariants, which were introduced to
compute the branching index of alkenes [14]. Kier and Hall extend-
ed these indices and introduced valence connectivity indices to
differentiate heteroatoms. These have now been applied success-
fully to a variety of physicochemical and biological activities [18].
Randic [19] suggested some features for TIs: (i) they must have
good correlation with at least one property; (ii) should have
structure interpretation; (iii) should be simple and independent;
(4) easy to apply to a local structure; (5) independent of experi-
mental properties; and (6) independent of others descriptors.
Fortunately, most of these features are found in the topological
descriptors. Hence, they have been prolifically applied in QSAR/
QSPR modeling to characterize the structural similarity or dissimi-
larity of chemical compounds.
Over the past few decades, advances in computational
approaches combined with contemporary methods have led to
an array of novel descriptors. In 2007, Topological Maximum
Cross Correlation (TMACC) was generated from atomic properties
determined by molecular topology [20]. These descriptors are
based on concepts that are derived from autocorrelation descrip-
tors. Spowage et al., illustrated the interpretability of the TMACC
descriptors by QSAR modeling of angiotensin-converting enzymes
(ACE) and dihydrofolate reductase (DHFR) inhibitors. Overall,
TMACC revealed features that were specific for C domain-selective
ACE inhibition, which was an improvement on previous QSAR
studies [21].
Geometrical descriptors are calculated from the 3D coordinates
of atoms in the given molecule. These descriptors are rich in
information and discrimination power for similar chemical struc-
tures and molecule conformations compared with topological
descriptors [22]. Moreover, they also include information obtained
REVIEWS
from atomic van der Waals areas and their overlap on the molec-
ular surface. Despite their high information content, these descrip-
tors usually also have disadvantages. Geometrical descriptors
require geometry optimization and, therefore, the overhead to
calculate them. Thus, for flexible molecules that can have several
molecule conformations, new information is available and can be
exploited. However, this leads to the problem that complexity can
increase significantly. Moreover, most of these descriptors (grid-
based descriptors) need alignment rules to achieve molecule com-
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parability. Several classes of descriptor can be distinguished within
the set of geometrical descriptors [22]. We have listed some of the
commonly used topological and geometrical descriptors along
with their formal description in Table 1. Most of the computa-
tional resources have gained significant popularity among
researchers for the definition of these descriptors and are consid-
ered as simple means of viewing molecular structures. Several
programs for calculating different molecular descriptors are listed
in Table 2.
Physicochemical descriptors
These are physical and chemical properties of a molecule that can
be estimated by examination of its 2D structure. These properties
have a major role in determining the concentration of drug in the
body. Appropriate properties of a drug can increase its efficacy and,
hence, its market value. Thus, studying these properties of a drug
not only supports the safety profile of the drug, but also has a
major role in assisting drug discovery by optimizing the com-
pounds selected. Therefore, there is a need to draw attention to
properties such as lipophilicity, solubility, and permeability, that
can ensure optimal potency, in addition to selecting the candidate
compounds with appropriate physicochemical properties.
The lipophilicity of a drug molecule refers to its affinity in a
lipophilic environment. It is a key property in the transport of
drugs in the body, including intestinal absorption, membrane
permeability, protein binding, and distribution among different
tissues [23]. A calculated log P is used as an assessment of lipophi-
licity in vivo, which reflects the key event of molecular desolvation
during transfer from aqueous phases to cell membranes and
protein-binding sites [24]. The required lipophilicity values for
drug candidates are general to a degree, specifically highlighting
the attraction of c log P values <5. Comparing the available oral
drugs with compounds at earlier stages of development showed
that high lipophilicity (>5) increased the chance of poor solubility
and in vivo toxicity. By contrast, a drug generally shows poor
ADMET properties in the vicinity of low lipophilicity [24]. The
accurate and efficient calculation of log P is crucial for virtual
screening because inaccurate values lead to imprecise results that
can cause potentially promising compounds to be discarded.
Various studies have been performed to show the relation between
lipophilicity and pharmacokinetic properties [24,25]. Waring [26]
surveyed the relevant literature for methods predicting lipophili-
city with ADMET parameters. The author showed that the optimal
range of lipophilicity lies between 1 and 3. Generally, two
methods have been used for calculating log P values: (i) the
fragment method, which is based on the contribution of function-
al groups and fragments attached to a nucleus of molecule for the
estimation of c log P value [27]. The most widely used fragment
method program is c log P, which contains a relatively small set of
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TABLE 1
Descriptors used in QSAR/QSPR model building.
Year Index Author(s) Description Refs
Topological (2D) descriptors
1947 Wiener (W) Wiener Defined as the sum of edges in the shortest path in a chemical graph [11]
between all pairs of nonhydrogen atoms in a molecule
1971 Hosoya (Z) Hosoya The number of sets of nonadjacent bonds in a molecule, useful for [67]
building the QSAR and QSPR models describing the physical properties
1972 Zagreb indices Gutman The first topological indices used for the total p-energy of conjugated [17]
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molecules
1975 Connectivity Randic The first-order connectivity index is a bond additive molecular structural [14]
invariant. Such indices have wide applications in structure–property and
structure–activity studies
1975 Higher order connectivity Kier et al. Higher order connectivity indices are weight paths, where the higher [68]
weight has been assigned to terminal bonds and a lesser weight to the
less exposed inner bonds
1980 Autocorrelation indices Moreau-Broto First introduced to define a relation between atoms as a function of their [69]
spatial separation; have certain advantages for any QSAR/QSPR study:
fragment independent; invariant to roto-translation; encode the identity
and electronic attributes, including atom types, partial atomic charges,
electronegativity, and polarizability
1982 Balaban J Balaban Distance connectivity index, or average distance sum connectivity, is also [16]
one of the most discriminating molecular descriptors. Its value is
independent of molecular size or number of rings
1985 Kappa shape Kier Shape of molecules defined in terms of number of atoms and their [70]
bonding pattern. Present in various orders (e.g., first, second, third order,
etc.); first order index involves a count of single bonds, whereas second
order index involves a count of a two bond path, and so on
1993 Hyper-Wiener index WW Randic Hyper-Wiener index WW of a chemical tree T is defined as the sum of the [71]
products n1n2, over all pairs u, of vertices T
1994 Szeged (Sz) Gutman Obtained as a bond additive quantity in which bond contributions are [72]
given as the product of the number of atoms closer to each of the two
points of each bond
2001 Modified Hosoya index Z* Randic Frequency of occurrence of individual CC bonds in the patterns of disjoint [73]
bonds are considered
2001 Modified Wiener index W* Nikolic et al. Bond contributions determined using the reciprocal of the product of the [74]
number of atoms on each side of a bond
2003 Novel Wiener index Li et al. Obtained as a bond additive quantity in which bond contributions are [75]
given as the product of the number of atoms closer to each of the two
points of each bond
2007 Topological Maximum Melville et al. Generated from atomic properties determined by molecular topology. [20]
Cross Correlation (TMACC) These descriptors are based on concepts derived from autocorrelation
descriptors
2010 Augmented Zagreb index (AZI) Furtula et al. Based on the atom-bond connectivity (ABC) index, used for obtaining the [76]
extreme AZI values for chemical trees; applicable for tight upper and
lower bounds of chemical trees
2011 Superaugmented eccentric Gupta et al. Fourth-generation topological indices (TIs) exhibiting high discriminating [77]
distance sum connectivity power, low degeneracy, and high sensitivity toward both the presence
and relative position of heteroatom(s)
Geometrical (3D) descriptors
1977 3D-Molecular representation of Soltzberg and Wilkins MoRSE descriptors have been shown to have good modeling power for [78]
Structures based on Electron different biological and physiochemical properties and can be used for
diffraction (MoRSE) the simulation of infrared spectra
1994 Weighted Holistic Invariant Todeschini et al. WHIM descriptors are used to capture the relevant 3D information [22]
Molecular (WHIM) regarding the molecular size, shape, symmetry, and atom distribution;
have been used for modeling toxicology and various physicochemical
properties. At least ten different WHIM types (e.g., WSIZ, WSHA, WDEN) of
descriptors with different molecular features have been developed
1995 3D Autocorrelation Wagener et al. These descriptors are calculated by applying the autocorrelation function [79]
at distinct points on molecular surface. They are unique for a given
geometry, sensitive conformational change, and are invariant to roto-
translation
2002 GEometry, Topology, and Consonni et al. GETAWAY descriptors are based on spatial correlation formula that give [22]
Atom-Weights AssemblY weight to the atom to count atomic mass, van der Waals volume, and
(GETAWAY) electronegativity along with 3D information. Based on matrix operator
and information indices, seven GETAWAY descriptors have been reported
so far

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Drug Discovery Today  Volume 21, Number 8  August 2016 REVIEWS

TABLE 2
Software for calculating the descriptors and fingerprints.
Software Descriptors Type of descriptors Web address Status
ACD/labs – log P, log S, log D, pKa www.acdlabs.com Commercial
ADAPT 260 Topological, geometrical, electronic, www.research.chem.psu.edu Freeware
physicochemical
ADAPT 260 Topological, geometrical, electronic, http://research.chem.psu.edu/pcjgroup/adapt.html Freeware
physicochemical

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ADMET predictor 297 Constitutional, functional group counts, www.simulations-plus.com Commercial
topological, E-state, 3D descriptors,
molecular patterns, acid-base ionization,
empirical estimates of quantum
ADRIANA. Code 1244 Constitutional, functional group counts, www.molecularnetworks.com Commercial
topological, E-state, Moriguchi, Meylan
flags, 3D descriptors, molecular patterns,
etc.
ALOGPS2.1 – log P, log S www.vcclab.org Freeware
CDK – Topological, geometrical, electronic, http://cdk.github.io Freeware
constitutional
ChemDes – Molecular descriptors www.scbdd.com/chemdes Webserver
(Freeware)
CODESSA 1500 Constitutional, topological, geometrical, www.codessa-pro.com Commercial
charge-related, semi-empirical,
thermodynamical
DRAGON 4885 Constitutional, topological, 2D- www.talete.mi.it Commercial
autocorrelations, geometrical, WHIM,
GETAWAY, RDF, functional groups, etc.
E-DRAGON – Molecular descriptors www.vcclab.org/lab/edragon/ Freeware
JOELib 40 Counting, topological, geometrical www.ra.cs.uni-tuebingen.de Freeware
properties, etc.
MODEL 3778 Molecular descriptors http://jing.cz3.nus.edu.sg/cgi-bin/model/model.cgi Webserve
(Freeware)
MOE 300 Topological, physical properties, structural www.chemcomp.com Commercial
keys, etc.
MOLCONN-Z 40 Topological www.edusoft-lc.com/molconn Commercial
MOLD2 779 1D, 2D www.fda.gov Freeware
MOLGEN-QSPR 707 Constitutional, topological, geometrical, www.molgen.molgenqspr.html Commercial
etc.
OEChem TK – 166-bit MACCS, LINGO, Circular, Path www.eyesopen.com –
(Daylight-like)
OpenBabel – MOLPRINT2D, 166-bit MACCS, Daylight www.openbabel.org Freeware
fingerprint (FP2), structural key
fingerprints
PADEL 1875 1D, 2D, 3D descriptors, molecular www.padel.nus.edu.sg Freeware
fingerprints
PowerMV 1000 Constitutional, atom pairs, fingerprints, www.niss.org/PowerMV Freeware
BCUT
PreADMET 955 Constitutional, topological, geometrical, http://preadmet.bmdrc.org Freeware
physicochemical, etc.
Sarchitect 1084 Constitutional, 2D, 3D www.strandls.com/sarchitect/index.html Commercial

fragment values obtained from accurately measured experimental
log P data for a small set of simple molecules; and (ii) an atom-
based approach, which involves estimation of log P based on the
classification of atoms into chemically distinct types and fitting of
the contributions to a data set of experimentally determined log P
values [23,27]. Several software packages are available for the
calculation of log P, and mainly rely on fragment-based
approaches (Table 1).
Given the complexity of the underlying physiological mecha-
nisms, the accurate prediction of drug permeability is a challenge
for in silico models. Several studies have been performed on in vitro
cellular permeability that showed its dependency on lipophilicity

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along with other factors, such as molecular size, hydrogen bonds,
hydrophilicity, and degree of ionization. These factors are known
to have a significant role in the intestinal absorption of a molecule.
The BCS (Biopharmaceutics Classification System) for higher per-
meability is defined as >90% for higher intestinal absorption. If
the absorption rate is less than the defended value, then the drug is
considered to have low permeability. Molecular size is an impor-
tant factor affecting intestinal absorption and biological activity.
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Compounds with hydrophobicity (LogDpH7.4 = 0–2) and interme-
diate size (MW = 500) are known to permeate the intestinal wall by
passive transcellular diffusion [6,28]. A model for predicting intes-
tinal permeability was developed using different physicochemical
descriptors. It showed that hydrogen bond donors and lipophili-
city are significant in the prediction of human intestinal perme-
ability [28]. In 2011, Alex et al. studied the impact of
intermolecular hydrogen bonding to improve membrane perme-
ability and absorption beyond the rule of five chemical spaces. It
was hypothesized that intermolecular hydrogen bonds in drug
molecules shield polarity, facilitating improved membrane per-
meability and intestinal absorption of cyclic as well as noncyclic
beyond rule of 5 (BRo5) compounds [29]. MW has been correlated
with decreased permeability. Increased lipophilicity (c log P) typi-
cally improves permeability. However, increasing the c log P
decreases the solubility and increases the promiscuity and toxicity
of a drug [30]. Therefore, there is a need for permeability measure-
ments that can be used for early screening sets or library designs,
lead optimization, and preclinical candidate selection. To measure
the permeability, new experimental and computational models
are needed that are able to handle a large amount of data. Numer-
ous in silico-based algorithms and multivariate tools (i.e., PLS,
ANN, SVR, and RF) are currently used for the prediction of per-
meability, as for solubility [31]. A review by Matsson et al. provides
the recent developments in the computationally prediction of the
permeability [30].
Poor aqueous solubility is a major cause of failure for any drug
development process. It is estimated that around 70% of drugs in
development are poorly soluble, with 40% of those currently
approved also being poorly soluble. The solubility of a substance
is the amount that can be dissolved in a given volume of solvent at
a specified temperature. A compound is considered to be highly
soluble if its immediate dose dissolves in 250 ml in the pH 1–7.5.
Aqueous solubility has an important role in the release of drugs
and their permeability through biological membranes, and their
transport and absorption. A QSAR study was conducted on 191
drug-like compounds from the AQVASOL database using a set of
simple structural and physicochemical properties to predict the
aqueous solubility [32]. The study concluded that solubility
decreases with increasing molecular size, rigidity, and lipophili-
city. Several methods have been reported for the prediction of
aqueous solubility [33–35]. A review by Johnson and Zheng [36]
discussed a significant role for, and progress in, computational
models for the prediction of aqueous solubility and absorption of
drug compounds.
Descriptor selection methods
To remove irrelevant descriptors, a selection criterion is required
that can measure the relevance of each selected descriptor with the
output of any classifier. Fig. 2 depicts the procedure that can be use
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Drug Discovery Today  Volume 21, Number 8  August 2016
for the selection of the descriptors. Such descriptor selection
techniques have become an obvious requirement in development
of the robust QSAR models. The interpretability and generality of
the models obtained by these methods are highly dependent on
the statistical relations among the descriptors and target proper-
ties. Thus, expert knowledge in the selection process is required to
gain user confidence in the selected set of descriptors. Recently,
Martı́nez et al. developed a tool named Visual and Interactive
DEscriptor ANalysis (VIDEAN) that combines statistical methods
with interactive visualizations for choosing a set of descriptors
[37]. They used the expertise of chemists in an interactive visual
exploration of different pieces of data generated from statistical
and information theory-based metrics. The significance outcomes
using this method are: descriptors with discriminative informa-
tion, redundant descriptors, and descriptors whose knowledge
helps reduce the uncertainty about the value of the target proper-
ty. In another study, Haggarty et al. applied metric space maps for
molecular descriptors of deacetylase inhibitors by using the prin-
cipal component analysis (PCA) and 3D visualization and revealed
that subspaces have different densities of biological activity [38].
The results provide evidence that certain structural features are
significant for activities of deacetylase inhibitors with respect to
their biological targets. Three main strategies that can be used for
the selection of relevant descriptors subset are the Filter, Wrapper,
and Embedded (or hybrid) methods. Fig. 3 provides the character-
istics, advantages, and disadvantages along with examples of these
three strategies.
Filters select subsets of descriptors as a preprocessing step,
independently of an induction algorithm. In this method, a
feature relevance score is calculated, and low-scoring features
are removed [39]. Filter methods consider the feature indepen-
dently, or in terms of the dependent variable. The main advan-
tages of using this method are that it is simple, quick, requiring
little computational time, and independent of the classifier used;
however, it has the disadvantage that it does not interact with the
classifier. Several techniques, such as Euclidean distance, Mutual
information (MI), and correlation methods, can be used as filter
methods. MI is the most widely use concept from information
theory and has been used to capture the relevance and redundancy
among features. MI in combination with genetic algorithms has
also been successfully applied to descriptor selection for QSAR [40].
The disadvantage of this method is that it depends on the estima-
tion of the probabilities (estimated from training samples) for
activity [41].
The Wrapper method selects the best features subset guided by
the error of the classifier function for a given subset. The perfor-
mance of the wrapper approach is better compared with that of the
filter approach. However, the former method is expensive in terms
of computational complexity and time because each feature subset
is evaluated with the classifier algorithm used. Wrapper methods
only use a single classifier. Given that each classifier has its own
biases, each will select different feature subsets. To address the
problem of classifier bias, a study investigating the effects of
different classifiers for wrapper feature selection revealed that
the number and nature of classifiers greatly affect feature selection
results [42]. A range of strategies, such as a random hill-climbing
algorithm, or heuristics, such as forward selection, backward
elimination, and stepwise regression, can be used to add and