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Mini-Reviews in Medicinal Chemistry, 2014, 14, 35-55 35

Recent Advances in Multidimensional QSAR (4D-6D): A Critical Review

Manoj G. Damale1, Sanjay N. Harke1, Firoz A. Kalam Khan2, Devanand B. Shinde3 and
Jaiprakash N. Sangshetti*2

1
Department of Bioinformatics, MGM’s Institute of Biosciences and Technology, Aurangabad (MS) India-431003;
2
Y.B. Chavan College of Pharmacy, Dr. Rafiq Zakaria Campus, Rauza Baugh, Aurangabad (MS) India-431001;
3
Department of Chemical Technology, Dr. B.A.M. University, Aurangabad (MS) India-431004

Abstract: The quantitative structure activity relationship (QSAR) study is the most cited and reliable computational
technique used for decades to obtain information about a substituent’s physicochemical property and biological activity.
There is step-by-step development in the concept of QSAR from 0D to 2D. These models suffer various limitations that
led to the development of 3D-QSAR. There are large numbers of literatures available on the utility of 3D-QSAR for drug
design. Three-dimensional properties of molecules with non-covalent interactions are served as important tool in the selection
of bioactive confirmation of compounds. With this view, 3D-QSAR has been explored with different advancements like
COMFA, COMSA, COMMA, etc. Some reports are also available highlighting the limitations of 3D-QSAR. In a way, to
overcome the limitations of 3D-QSAR, more advanced QSAR approaches like 4D, 5D and 6D-QSAR have been evolved.
Here, in this present review we have focused more on the present and future of more predictive models of QSAR studies.
The review highlights the basics of 3D to 6D-QSAR and mainly emphasizes the advantages of one dimension over the
other. It covers almost all recent reports of all these multidimensional QSAR approaches which are new paradigms in drug
discovery.
Keywords: Biological activity, Molecular descriptors, Multidimensional QSAR, Physicochemical property, QSAR.

INTRODUCTION model which indicates the association between molecular

The account of Rational Drug design starts with the
discovery of lead molecule by trial-and-error process or
screening the library of lead compounds [1]. Nowadays, a
Quantitative Structure Activity Relationship analysis is mostly
used in high-throughput screening of combinatorial libraries
of small chemical compounds and moved further to check
the activity of a diverse set of designed small compounds
[2]. The QSAR is a knowledge-based method where a statistical
prediction model is made about biological activity and the
presence of molecular descriptor. The aim of carrying out a
QSAR study is with the help of computational methods the
QSAR model can help evaluate biological activity; this is
mostly done to reduce failure rate in the drug development
process [3]. The historical aim of QSAR studies is to predict
the specific biological activity of a series of test compounds.
Nowadays the main objective of these studies is to predict
biological activity of Insilico-designed compounds on the
basis of already synthesized compounds [4].
In a QSAR study molecules are characterized based on
the presence of molecular descriptors and these descriptors
are mostly used to calculate the basis of physicochemical
properties of ligand molecule such as logP, pKa, mol. wt,
logD, molecular refractive index, molecular surface area,
molecular interaction field, etc. The constructed mathematical
*Address correspondence to this author at the Dr. Rafiq Zakaria Campus,
Y.B. Chavan College of Pharmacy, Aurangabad-431001 (M.S.), India;
Tel:/Fax: +91-240-23801129; E-mail: jnsangshetti@rediffmail.com
descriptors and biological activity, is validated internally and
externally in order to assess the predicative power of the
QSAR model (Fig. 1). The interpretations of these models
are carried out by various methods like pattern recognition,
machine and artificial intelligence. The first structure activity
relationship study was conducted in the late eighteenth
century when different alkaloids were studied, by Crum-
Brown and Fraser. To demonstrate the alkylation of basic
nitrogen, of a ring system results in the formation of quaternary
t-amine compounds which are different from basic amines,
and that now have significant change in its biological action.
Since then a variety of quantitative structure activity relationship
studies have been reported to predict cytotoxicities, depressant
and antibacterial activity of chemical compounds [5-7].
Thousands of QSAR equations have been formulated
using the QSAR methodology to validate and elucidate the
predicative power of QSAR hypothesis about the mechanism
of action of drugs at the molecular level and a more complete
understanding of physicochemical phenomena such as
hydrophobicity. In 1962 Hansch and Muir published their
brilliant study on the 2D structure-activity relationships of
plant growth regulators and their dependency on Hammett
constants and hydrophobicity [2]. The present review covers
all recent developments in the field of QSAR.
SCHEME OF QSAR STUDY
The QSAR model studies are mostly carried out in three
different steps.

1875-5607/14 $58.00+.00 © 2014 Bentham Science Publishers

36 Mini-Reviews in Medicinal Chemistry, 2014, Vol. 14, No. 1 Damale et al.

Fig. (1). Schematic overview of the QSAR process.

i. Understanding and Selection of Potential Molecular Table 1. List of desirable attributes of molecular descriptors
Descriptors from Set of Biologically Active Conformers for use in QSAR studies.

Understanding and selection of potential molecular

descriptors from set of biologically active conformers is Sr. No. Desirable Features Associated with Descriptors
most critical step in QSAR model generation as it helps to
understand the nature of molecular descriptors prior to actual 1. Structural interpretation
QSAR model construction. This mostly helps to reduce
2. Show good correlation with at least one property
un-necessary error in study data. The specified properties of
chemical compound are used to select the potential molecular 3. Preferably allow for the discrimination of isomers
descriptors like physicochemical properties; quantum-chemical,
geometrical and topological (Table 1). As we do select the 4. Applicable to local structure
potential molecular descriptor the necessary biological
5. Generalizable to “higher” descriptors
information will be obtained from them.
6. Independence
One of the earliest approaches for selection of molecular
descriptor by manual inspection was plotting a (2D) plot of 7. Simplicity
important molecular descriptor of bioactive conformers. And
as of then several methods have developed but first and most 8. Not to be based on properties
important computational method was cluster analysis
9. Not to be trivially related to other descriptors
developed by Hansch which made easier to select compounds
with diverse substituent on it [7]. Selection of relevant 10. Allow for efficient construction
molecular descriptors is covered under 1D-QSAR model.
11. Use familiar structural concepts
1D-QSAR
12. Show the correct size dependence
Various parameters are used to select the potential
molecular descriptor that defines the specific molecular 13. Show gradual change with gradual change in structures
properties of conformer like electronic constraints, hydrophobic
constraints and steric constraints. Hammett was the first to study the electronic nature of
a. Electronic Constraints chemical compound in case of benzoic acid ionization with
water in a chemical reaction to determine activation energy
The main aim behind the calculation of electronic effect (G). The various substitutions at meta and ortho positions
is to know about inter and intra- molecular interactions, with the help of electron-withdrawing and donating groups
which significantly contribute to biological action. Here the are studied. The analysis of both reactions was done, which
common constant in the QSAR equation is studied, i.e. helps in understanding that electron donating groups will
Hammett constants which include quantum chemical indices assist the rate of reaction. From the above observation one
such as the lowest unoccupied molecular orbital, the highest can make meaningful correlation about change the in the
unoccupied molecular orbital and polarizabilty.
Recent Advances in Multidimensional QSAR (4D-6D): A Critical Review
electronic nature of substituent and change in the activation
energy.
As the QSAR methodology developed most intensively
with the help of the computational method, the electronic
nature of chemical compounds is now studied as a wave
function using methods like calculation of quantum chemical
descriptor and the semi-empirical method. The quantum
chemical descriptor method uses constraints such as net
atomic changes, highest occupied molecular orbital/lowest
unoccupied molecular orbital (HOMO-LUMO) energies,
frontier orbital electron densities, and super delocalizabilities
to correlate these it with biological activity.
b. Hydrophobic Constraints
Hydrophobicity of a compound refers to the physicochemical
nature of that compound mostly in connection with the solvent.
The first QSAR study of hydrophobic property was conducted
in case of growth hormone by Hansch. There are many areas
where this property is studied: ligand-receptor interaction,
for example solvent interaction in case of detergency,
coagulation, membrane permeation and many more.
The hydrophobic nature of solute molecule across the
solvent is mostly studied by measuring the partition coefficient
P, where P is the ratio of concentration of solute present in
polar and non-polar solvents. The shake flask method is
commonly used to measure the P of a compound in the form
of logP value ranging from -3 to 6. There is inconsistency in
the manual measurement of accurate logP value so it has
been replaced by the automated system ClogP.
c. Steric Constraints
Steric effect of a molecule arises when a chemical compound
attempts to take certain space and this is because of its
charge or its specified shape or size. The steric nature is an
important phenomenon to study the transport of chemical
moiety across bio-membranes. R.W. Taft was the first to study
who studied the steric effect of a compound and termed it as
Es. Some important parameters that address steric effect more
effectively are molar refraction (MR) and molecular volume.
Molar refraction of the compound is studied in the form of
refractive index which measures the overall bulk of a
compound. However, as the reports of several studies show
measuring molar refraction of the compound did not allow
distinguishing between some shapes of alkyl substituents;
hence, molar refraction has been replaced by STERIMOL
parameters. These STERIMOL parameters give an overall
account of the dimensions of compound like length of the
substituent or the bond angle between substituents. In this the
steric effect of a compound at several fixed axes is studied. The
3D steric property can be studied for both substituent and
parent compound by studying parameters such as bond length
and bond order.
Parameters such as the length of the substituent and bond
length between the parent and the substituent are taken into
consideration and by including all these parameters in the
study, chemical compound can be studied three dimensionally.
Molecular volume of the compound affects on bulkiness
study by affecting the transport of moiety across the cellular
membrane [2].
Mini-Reviews in Medicinal Chemistry, 2014, Vol. 14, No. 1 37
ii. Analysis of Potential Molecular Descriptors in the
Context of Analysis of Activity
The correlations of biological activity to physicochemical
property are made by using the manual method by forming a
linear relationship between them [8]. The effects of Hammett
and Taft constant are studied for biological activity. The
numbers of equation are generated to significantly intercorrelate
the activity using a narrow gap between the number of
descriptors and the set of dataset. Once the set of molecular
descriptors is selected from them most informative sets can
be used for the study.
iii. Mapping the Specified Value Obtained for Each
Descriptor and Feeding as Independent Variable to
Correlate With Its Biological Activity
The analyzed sets of molecular descriptors which are
used for mapping either by linear or nonlinear mapping
techniques. The quantified values of each descriptor are used
as a function of activity. Many times the methods used for
carrying out mapping utilize the information about a training
set to obtain the optimal function [7].
2D-QSAR
The 2D-QSAR study is mostly based on specialized
molecular fragments that constitute the chemical compound.
Mostly, there are different descriptors that include constitutional,
topology, total polar surface area, electrostatic and quantum-
chemical, geometrical and molecular fingerprints property of
the chemical compound [9, 10].
a. Constitutional Descriptors
These are the descriptors that reflect the constitutional
property of a chemical compound without dealing with
connectivity or geometry of the chemical compound. These
descriptors are molecular weight, number of atoms, number
of hydrogen, number of carbon, number of halogen, number
of oxygen, number of nitrogen, number of ring system, number
of bond like, number of single bond, number of double bond,
number of triple bond as well as number of aromatic bond
and many more [7].
b. Topological Descriptors
The topological descriptors mostly deal with the
arrangement of chemical compound which defines the
information of a compound like orientation of the internal
bond, molecular size, shape, branching and presence of
hetero-atoms [7]. Overall the topology of a compound is
mentioned in the form of 2-D graph like nodes and edges.
There are several indices that are used to signify the
molecular connectivity of the compound and are categorized
as topochemical and topostructural indices. These indices
include the Wiener index, the Randic index, the Balaban J
index, the Scultz index, the Kier and Hall index, the Galvez
topological charge index, the BCUT Eigen value index, the
E-sate index and so on [7, 11]. All of the above-mentioned
indices define the overall connectivity, average distance,
average valence, net charge transfer, bond polarizabilty,
electronic and topological organization of atom in the form
of nodes and bond in the form of edges. Topological index is
also very helpful in determining the structure and substructure
38 Mini-Reviews in Medicinal Chemistry, 2014, Vol. 14, No. 1
in case of chemical database mining where structure similarity
and diversity are measured in a set of structural data using
precise computational algorithm [12].
c. Topological Polar Surface Area
The topological polar surface area (TPSA) is the most
conveniently used term in case of ADME prediction of
chemical compounds. TPSA is also commonly exploited to
measure the relative propensity of ligand molecules, for polar
interaction in specific receptor molecule, but still TPSA is
the least commonly exploited term. The methods like multiple
linear-regression analysis have been employed to study
TPSA. Analysis of coefficient of linear–regression will help
us know the polar fragments in a compound favoring or
disfavoring the biological activity [13].
d. Quantum Chemical Descriptors
Quantum chemistry method in combination with recently
developed efficient computational algorithms is used to
study quantum mechanical calculations. These calculations
are mostly focused on electronic and geometrical properties
of molecules. Because of this reason most of the time
electrostatic and quantum chemical descriptors are studied in
combination. The mostly used quantum chemical descriptors
in QSAR studies are atomic charges, molecular orbital
energies, frontier orbital densities, atom-atom polarizabilty,
molecular polarizabilty, dipole moment and polarity indices,
total energy and many more. Quantum chemical methods are
very fast and accurate methods and mostly neglect the
solvent effect, so the results obtained from the quantum
chemical method are most valid and can be directly applied
for correlation with biological activity [7].
e. Geometrical Descriptors/Molecular Fingerprint Descriptors
Molecular fingerprint descriptors are used to represent
the molecular properties of a compound. There are two
methods using which molecular fingerprint can be calculated:
one based on fragment dictionary and another is the hash
method (binary bit string). In hash method, each bit is a
pattern which that represents the characteristic of molecules
like structural fragment, connectivity of the molecule and
pharmacophoric nature. Each bit is encoded in the form of
binary format with a specific value. These molecular
fingerprints are mostly used for searching of molecules
“similar” to a query molecule; for example, Daylight chemical
information system fingerprint is a unique subgraph search
algorithm that works on the path-based approach. This
algorithm works on learning from the set of training
molecular fingerprint of unique connection path (subgraph)
to a large bit string (maximum of eight bit) [7]. In 1982,
Molecular Drug limited (MDL) started a program that helps
in storage and retrieval of chemical reaction information.
MDLs create a key or compact set of fingerprints, where
predefined observations are used to create a pattern matching
fingerprint. The pre-defined data search learning is carried
out using a large dataset of chemical compounds present in
the MDL databank (320 keys from their 966 sets). Barnard
Chemical Information Systems (BCI) is another predicative
fingerprint model that works by on first predicting the
fingerprint and then implementing it like the presence or
absence of certain fragment of molecule. Typically, BCI
Damale et al.
generates numbers of key fingerprints corresponding to a
feature of molecule like the nearest neighborhood atom pair,
bonded sequence of atom, the specific fragment of ring, etc [14].
1D vs. 2D-QSAR
1D-QSAR is a “classical” form of the QSAR, mostly
focused on macroscopic properties of chemical compounds,
by representing them in the 1D linear form for example,
molecular formulas [15]. Predefined variables are calculated
by hand count or a pocket calculator where the concept
works on the classical approach given by Hansch. The numbers
of additive properties and indicator variable are used to
construct the QSAR model [2, 16].
The 2D-QSAR is more superior to the classical approach
[17]. Topological encoded information is enough to construct
the model. The limited numbers of additive and indicator
variables are used to construct the QSAR model [7]. It is
very easy and fast to calculate the encoded information
related to molecular architecture [12]. The 2D-QSAR is a
knowledge-based approach that requires some constitutional
information about the compound while constructing the
model [18]. The linear and nonlinear methods like multiple
linear regression method, GA, GA-PLS and PLS are used to
predict the QSAR model [19]. The steriochemical information
about the compound is not required by the model as it is built
on 2D properties of compounds. It gives better value for a
correlation coefficient than actual QSAR model prediction.
The six subtle principles are set by Organization for Economic
Co-operation and Development (OECD), and 2D-QSAR
satisfies all the principles except for mechanical interpretation.
The 2D-QSAR also suffers from problems such as lack of
interoperation or recognition ability in search of active
compounds. The 2D-QSAR prediction method also has a
limitation in the prediction of stereochemistry of a training
dataset selected in the study [20].
3D-QSAR
Three dimensional quantitative structure activity
relationships focused broadly on all such properties of
atoms in a compound that are represented as descriptor and it
mainly corresponds to spatial representation of a molecule
[21]. In early 1980, a novel approach in structure activity
relationship study was put forward, which include the study
of molecular properties of chemical compounds in a 3D grid
box. The calculated molecular properties are then subsequently
correlated with biological activity, using a technique called
DYLOMMS (dynamic lattice oriented molecular modeling
system) [22]. These properties are innate in nature and are
prolonged due to their molecular framework and mainly are
geometrical, electrostatic and quantum in nature. The mentioned
properties were first studied by Hansh et al. using a multi-
linear regression equation. The prediction of biological
activity of chemical a compound is mostly done based on
detailed information of receptor and ligand molecules.
However, in many cases 3D information of receptor molecules
was not known, and in these cases the indirect method of
3D-QSAR is mostly followed. The indirect approach of 3D-
QSAR is based on information of the ligand molecule such
as molecular alignment of atoms, pharmacophores, volume,
or fields to generate a virtual receptor [23].
Recent Advances in Multidimensional QSAR (4D-6D): A Critical Review
A. 3D-QSAR DESCRIPTORS
The 3D-QSAR approach is advanced, well established and
the most exploited technique for structure activity relationship
study. The concept is focused on the prediction of biological
activities based on 3D properties of lead compounds by
using a series of linear and nonlinear analytical predicative
methods. The 3D-QSAR approach is simpler than the
traditional structure activity relationship study. The major
objective of a 3D-QSAR study is to improve the activity of
the lead compound by optimization and structural modification
[24].
The first step in a 3D-QSAR study is to collect or design
a representative starting 3D structures of ligand molecules
and thereafter refine them based on geometry and energy
values [7]. The mostly used methods for energy optimization
are semi-empirical, molecular mechanics, and quantum
mechanics [10]. In the next step a database of conformers are
created belonging to lead molecules. These are flexible in
nature and are available in multiple forms. These multiple
forms of compounds are included in the QSAR study. From
multiple conformers, peculiar bioactive conformers are searched
and selected for a particular study. The selection of bioactive
conformer is done based on knowledge-based methods like
experimental and theoretical by measuring the binding
affinity towards receptor molecules. The selected datasets of
bioactive compounds are then aligned uniformly using the
computational tool. Once all the conformers are aligned 3D
properties of a molecule like steric and electrostatic are
calculated using a lattice probe by placing the probe at
different location lattices. At each probe point, the molecular
structure can be measured with sets of numbers which are
called descriptors [24]. These numbers mostly represent
physicochemical and biological properties of a molecule.
The descriptor calculation can be done with (dependent) or
without (independent) the alignment of bioactive conformers
[7].
i. Alignment Dependent Descriptor Methods
There are several methods used in the calculation of 3D
descriptors focusing on molecular alignment prior to the
calculation of 3D descriptors. These methods calculate the
descriptor by mapping receptor atoms or ligand atoms or
complexes of receptor-ligand atoms. Various alignment-
dependent descriptors are Comparative Molecular Field
Analysis (CoMFA), Comparative Molecular Similarity Indices
Analysis (CoMSIA), Genetically Evolved Receptor Modeling
(GERM), Comparative Binding Energy Analysis (CoMBINE),
Adaptation of the Fields for Molecular Comparison (AFMoC),
Hint Interaction field analysis (HIFA) and Comparative Residue
Interaction Analysis (CoRIA) [7, 25, 26].
a. Comparative Molecular Field Analysis (CoMFA)
Comparative Molecular Field Analysis (CoMFA) helps
in building the quantitative relationship. This is molecular
field-based method and was developed by Cramer in 1988
[4]. This is a more selective method as compared to the
traditional classical QSAR methods. The first CoMFA study
was carried out in the case of steroid [27]. It mostly focuses
on ligand properties (steric and electrostatic) and ligand-
Mini-Reviews in Medicinal Chemistry, 2014, Vol. 14, No. 1 39
receptor interactions like favorable and unfavorable receptor-
ligand interaction. As previously discussed, CoMFA is an
alignment-dependent descriptor methods. All aligned ligands
are placed in energy grid and by placing the probe at each
lattice point, energy is calculated. The resultant energy
calculated at each unit fraction corresponds to electrostatic
(Coulombic) and steric (Van der Waals). These values serve
as descriptors for further analysis. These values are further
correlated with other biological activities using the linear
regression method like partial least square (PLS). PLS
results served as an important signal to identify the favorable
and unfavorable electrostatic and steric potential and also to
help correlate it with biological activity [24].
b. Comparative Molecular Similarity Indices Analysis
(CoMSIA)
Comparative Molecular Similarity Indices Analysis
(CoMSIA) is a recent modification of CoMFA. The approaches
of CoMFA and CoMSIA are similar, except for molecular
similarity which is calculated additionally [22]. The CoMFA
mostly focuses on the alignment of molecules and may
lead to error in alignment sensitivity and interpretation of
electrostatic and steric potential. To cut lose CoMSIA fields,
Gaussian potentials are used; they are much 'softer' than the
CoMFA functions. The regular energy grid box is constructed
and similar probes are placed throughout the grid lattice. In
addition to this solvent dependent molecular entropic term
which defines hydrophobic term also included in the study.
To analyze the property of dataset atom, a common probe is
placed and similarity at each grid point is calculated. The
calculation is mostly done on steric, electrostatic, hydrophobic
and hydrogen bonding properties. All of these properties are
calculated at regular spacings of grid point corresponding to
a particular descriptor and these are important in correlation
with biological activity [24].
c. Genetically Evolved Receptor Modeling (GERM)
Genetically Evolved Receptor Modeling (GERM) is a
theoretical knowledge-based method. The construction of a
3D structure of receptor active site is done by using Homology
modeling in the absence of experimental structure like X-ray
crystallography and NMR spectroscopy [28]. As an initial
step in the GERM 3D-QSAR, reasonable series of structure
activity relationship are selected and alignment of these
reasonable bioactive conformers is done. All the aligned
conformers are enclosed into the receptor active site and
allocating them as a shell of atoms. The allocated shells of
atoms are considered an explicit set atom (aliphatic H,
aliphatic C, polar H) and matched at the receptor active site
similar to those found in the receptor active site. Hence, the
shell of aliphatic carbon has been replaced by a uniform
sphere of an aligned training set. The position of model
aliphatic carbon atom and aligned ligand training set are
adjusted so that maximum Van der Waals interactions are
obtained. Once the position of aliphatic carbon has been
identified their position can be occupied by any other atom
or no atom. As practically, one could replace atom type with
spheres or combination of both can be used and as a result of
this large rendered model can be generated. To deal with this
problem and to a create number of possible conformers in to
40 Mini-Reviews in Medicinal Chemistry, 2014, Vol. 14, No. 1
the active site of receptor, genetic algorithm is used, where a
number of possible conformers of ligand molecules are
generated using the well-suited docking program. The
intermolecular bonding between the ligand and receptor
complex is calculated using advance force field like
CHARMM, which mostly computes electrostatic and Van
der Waals interaction. The calculated binding energy value is
then used to correlate with biological activities [29]. The
GERM technique is mostly suited for de novo drug design
process where above the mentioned-approach is followed
[30].
d. Comparative Binding Energy Analysis (COMBINE)
This method works on empirical knowledge-based method
where experimentally demonstrated complex of the receptor
ligand is used for further determination of molecular properties
to correlate with biological activity [31, 32]. As the name
suggests, this technique mostly focuses on the free energy of
binding of ligand molecules, and are calculated using molecular
mechanics force field. The series of complexes are observed
for intermolecular potential interaction like electrostatic and
Van der Waals as per residue in the active site. Another
alternative approach has been followed where ligands are
fragmented into similar fragments and each ligand molecule
is build by incorporating a dummy fragment into it that is not
essential and intermolecular potential interactions are
calculated. The energy is calculated for all pair of atoms in
receptor active site residue and ligand atom on the basis of
the distance-based method. The significant descriptors are
retained and others are eliminated for the study data. Then
statistical technique like PLS is used to generate the QSAR
model to quantify the most important energy interaction in
terms of activity prediction [24].
e. Adaptation of the Fields for Molecular Comparison
(AFMoC)
This is a very recently developed QSAR technique put
forward by Klebe et al. [4]. It is also called “Inverted CoMFA”
derived from potential scoring function (drug score). The
methodology of AFMoC is similar to that of CoMFA and
CoMSIA but the additional advantage is the involvement of
protein environment in the study. The protein-specific potential
fields are generated into binding sites, which are used for the
prediction of binding affinity [24, 33]. The overall methodology
of AFMoC is discussed below in three steps.
i. Potential Field Calculation and Ligand Alignment
Drug score is a new developed knowledge-based scoring
function based on distance-dependent pair-potentials. The
atom by atom pair-wise potential is calculated in case of
ligand and protein environments. These potential values are
calculated using a suitable probe at the intersection at each
grid point constructed around the binding pocket.
ii. Interaction Field Calculations
Potential field map generated for complexes of ligand
and receptor is used as an interaction field to calculate atom
type and distance-dependent interaction (3D Gaussian
functions) for each atom at each grid point.
Damale et al.
iii. Making Correlation between Interaction Field Value
Calculations and Binding Affinity Prediction
Theoretically calculated interaction field values are
correlated with experimentally determined biological affinity
for surrogated ligand molecules using PLS analysis [24, 34].
f. Hint Interaction Field Analysis (HIFA)
It is a newly developed program used to calculate
empirical hydrophobic interaction and extension of CoMFA.
As a result of the introduction of hydrophobicity calculation
in CoMFA, the predicative power of it for QSAR model has
increased. It calculates key hydrophobic features, which are
atom-based analogs of the fragment constant. It uses the
already-published data to predict hydrophobic field interaction.
The methodology of HIFA is to calculate hydrophobic field
interaction in the same manner as that of CoMFA by aligning
the ligands and then placing them into a grid, followed by
the interpretation of the net sum of hydrophobic interaction.
g. Comparative Residue Interaction Analysis (CoRIA)
Comparative Residue Interaction Analysis is a recent
invention in the field of 3D-QSAR studies. There are several
advanced modifications in CoRIA methodology like reverse-
CoRIA (rCoRIA) and mixed-CoRIA (mCoRIA) [35]. The
main emphasis of CoRIA study is to calculate and analyze
the receptor–ligand complex and thereafter predict the binding
affinity of the complex. The binding energies in the form of
non-bonded interactions like van der Waals and Coulombic
which describe thermodynamic events involved in ligand
binding to receptor, are calculated. These interactions are
correlated with biological activities using the G/PLS analysis
method, which is an advancement of the PLS method which
additionally covers several variables like lipophilicity, molar
refractivity, surface area, molecular volume, Jurs descriptors
and strain energy [36-38].
ii. Alignment-Independent Descriptor Methods
The conventional methods based on the alignment approach
have many limitations like they are time consuming, can
introduce user biasness and it may affect the sensitivity of
the resultant model. To overcome all these limitations a
novel class of method has been adopted, which is independent
of alignment and is not affected by radiation or transformation
of the molecule. The different methods belonging to this
category include Comparative Molecular Moment Analysis
(CoMMA), COMPASS, Holo-QSAR (HQSAR), Weighted
Holistic Invariant Molecular Descriptors (WHIM), Comparative
Spectral Analysis (CoSA) and Grid Independent Descriptors
(GRIND).
a. Comparative Molecular Moment Analysis (CoMMA)
The Comparative Molecular Moment Analysis (CoMMA)
is alignment independent descriptor method. The CoMMA
mainly focuses on 3D/spatial arrangement of molecular
fragment and calculates different molecular moment with
respect to center of mass, center of dipole and center of
charge. Descriptors for CoMMA are zero order descriptor
(molecular weight and moment of inertia with respect to
center of mass), first order descriptor (magnitude of dipole
moment (
)) and second order descriptor (quadruple moment
Recent Advances in Multidimensional QSAR (4D-6D): A Critical Review
(Q)) with respect to molecular charge. Secondly, dipole moment
components around the axes (x,y,z) and displacement d in
case of center of dipole and center of charge are calculated
using principle of inertial axes. All these are calculated by
taking reference frame (initial) into account who will
superimpose with center of dipole moment. Each value obtained
from calculation of principle of inertial axes for center of
mass, center of dipole and center of charge are used as
descriptors. Finally these descriptors are correlated with
biological activity using PLS analysis techniques [7, 39].
b. Compass
The quantitative structure activity relationship often uses
nonlinear method of correlation in activity because it mostly
predicts accurate activity as compared with linear method.
Compass work on concept of artificial neural network. The
compass focuses on features such as molecular surface and
conformation selection for alignment. The selection of
proper ligand shape is more significant because it mainly
flexible in nature and may adopt many conformations with
slight change in geometry. The alignment of conformation is
done and corresponding similar part is found. As said above
the conformation will be aligned in many ways and which
help in predicting biological activity. There is automatic
selection of bioactive conformation and creating a model of
alignment for each conformer.
The algorithm on which compass work is divided into
three phases, the initial phase is called as alignment of pose
where alignment of different conformation is done to find
bioactive one. Second phase is called as bioactive model
construction; this phase is focusing on facts like selection of
bioactive conformation and constructing statistical model
which uses properties of molecular features. The quantitative
relationship is established between molecular surface properties
and biological activity. The third phase is called as molecular
display, the relationship between molecular properties and
biological activity displayed and which will help in molecular
modeling [39-41].
c. Holo-QSAR (H-QSAR)
It is recently developed QSAR technique by Heritage and
Lowis (1997), which mostly focus on molecular fragments,
exploring the chemical and biological data of chemical
compounds. Each molecule is broken into the specified
unique form and there after these fragments are used to form
a Holo-gram. The molecular fingerprints have been defined
in a pattern of fragments that binds in predefined order of
array. These fingerprints are used to define nature and type
of molecular fragments. The three dimensional property of
the molecule are used to define hybridization and chirality.
Each corresponding molecular fragment has its peculiar
physicochemical properties and that will be correlated with
corresponding biological activities by using PLS analysis in
to order construct H-QSAR model [42].
d. Weighted Holistic Invariant Molecular Descriptors
(WHIM)
Weighted Holistic Invariant Molecular Descriptors
(WHIM) is recently developed and slightly different approach
of 3D-QSAR technique as compared to conventional approach.
Mini-Reviews in Medicinal Chemistry, 2014, Vol. 14, No. 1 41
It is mostly used to represent properties of 3D descriptors of
chemical structure in the form of indices. It contains the
information about ligand structure in the form of their size,
shape, symmetry and atom distribution. These indices are
calculated about Cartesians coordinates around x, y, z axis of
energy minimized ligand structure. These minimal energy
structures are subjected to weighting scheme has been applied
to describe them in the form of unitary conceptual framework.
The indices are used to search proper QSAR model. The
G-WHIM and MS-WHIM are modifications of WHIM
method where in case of G-WHIM (Grid-Weighted Holistic
Invariant Molecular) descriptors are calculated using gird.
The coordinates of each atom of grid are set and probe
interaction energy potential is calculated at each point. The
MS-WHIM called as molecular surface Weighted Holistic
Invariant indices, it mostly focuses on theoretical descriptors
which enabling the information like size, shape and electrostatic
distribution of a molecule [4, 7].
e. Comparative Spectral Analysis (CoSA)
Comparative Spectral Analysis (CoSA) has been
recently developed and not yet explored fluently except
few applications. In this technique molecular spectroscopy
methods have been used for determination of three dimensional
molecular descriptors of chemical compounds in 3D-QSAR
study. The molecular spectra used to predict biological activity
of three dimensional structures. The spectroscopic method
mostly includes are Proton (H)-NMR, carbon C13NMR, IR and
Mass spectrometry. The data generated through spectroscopic
studies are converted into matrices values with the help of
appropriate tool and then correlated with biological activity
by using PLS analysis. The comparative study of CoSA and
CoMFA has carried out to evaluate predicative nature of
CoSA and fortunately it gives better correlation values as
compared to CoMFA studies [43].
f. Grid Independent Descriptors (GRIND)
Grid Independent Descriptors (GRIND) is first method
developed as an alternative for method like CoMFA. The
basic approach of GRIND and CoMFA are same. Both
methods are grid based methods where probe is placed at
particular gird lattice around the three dimensional structure
of macromolecule complex. The non bonded interactions are
also calculated like electrostatic, steric and van deer Waals.
This technique has several advantages as it uses “DRY Probe”
to calculate HBD, HBA and Hydrophobic interaction.
Additionally it utilizes most softer/smoother potential
function method to calculate Van der Waals interaction. The
values of each potential probing point can be correlated with
biological activities by using multilinear regression like PLS
analysis [44, 7].
B. STATISTICAL APPROACHES FOR SELECTION
OF RELEVANT MOLECULAR DESCRIPTORS
Structure activity relationship study concepts mainly
focus on various chemical characteristics of chemical data
and from that it mostly focuses on the retrieval of a desired
set of information. To do this, wild spectrum of data analysis
method has been used, which works on various statistical
correlations. These data analysis methodologies are mostly
meant for recovery of primary and secondary information.
42 Mini-Reviews in Medicinal Chemistry, 2014, Vol. 14, No. 1
This information is about dependent and independent variables
in a correlation study, i.e. activity (y-variable) and molecular
descriptors (x-variable) [24].
i. Linear Regression Analysis
It is the first type of regression analysis and has more
application in the practical predicative method mostly used
for prediction of relationship between dependent and
independent variables (i.e. ss x and y). The simple linear
regression can be expressed by the following equation:
y= a + bx
where ‘a’ is called the intercept constant, ‘b’ the regression
coefficient, “x” is depicted as a molecular descriptor, which
is one or more than one in numbers and also called the
explanatory variable, whereas “y” is called as the dependent
variable and it mainly corresponds to activity in the QSAR
study. Here values of x and y variables are fed to the above
equation and linear regression analysis can be applied for
predicative analysis [24].
ii. Multiple Linear Regressions (MLR)
The LRA is used to predict the relationship between
variables in SLR equation, whereas MLR is used to determine
the quantitative relationship between them. It is also referred
to as the linear free energy relationship method; thus it is an
extension of SLRA [45]. Here 2D relationship between x and
y is defined using the SLR equation. The aim of applying the
SLR equation is the value of ‘a’ and ‘b’ in the equation
defining the best prediction of the x and y variables. There
are several best methods available for finding the correlation
between them like the Student t-test, standard deviation and
multiple correlation coefficients or the independent method
like the leave on out method. In MLR analysis the relationship
between x and y variable is expressed by modifying the
SMR equation and adding several new terms in it. The MLR
equation is as follows:
y = b0 + b1 x1 + b2x2 +………… + bm xm + e
where b1 is used to estimate the regression coefficients and e
is the minimizing residual error used to quantify deviation
from linear relationship on the regression line. The significance
of correlation is judged by calculating the correlation
coefficient and cross-validating it [24].
iii. Multivariate Data Analysis
The chemical data used in QSAR analysis are
multidimensional in nature where features of a chemical
compound are defined by many other data components [46].
The chemical data used in QSAR analysis are usually
multidimensional in nature, by means of which features of
the chemical compound can be defined by many other data
components. The multivariate techniques are specifically used
to reduce the multiple components within the data. The
techniques used are principle regression analysis (PCA), partial
least square analysis (PLS), genetic algorithms (GA) and
genetic algorithms- partial least square analysis (GA-PLS).
The statistical analysis of these features is represented using
the matrix that has row and column. Each of them represents
the property and features of chemical compounds [24].
Damale et al.
iv. Partial Least Squares (PLS)
This is an improved QSAR model predication technique
introduced by Hermann and Svante Wold. PLS is the most
commonly used technique in QSAR model analysis. It is
used to make a more attractive QSAR model because it predicts
a more realistic and complicated SAR data for biological
activity. It is also called the latent or projection structure
method. Here the large numbers of descriptors can be
transformed into a small number of new orthogonal terms,
called the latent variable. The numbers of latent variables are
used to define the dependent variable. The main aim of this
technique is to form a relationship between matrixes (features
and property). The SIPLS is the most commonly used
algorithm in the PLS technique. It is mostly used as a
predicative model of 3D-QSAR.
v. Genetic Function Approximation (GFA)
Genetic function approximation (GFA) is a new
computational algorithm derived from the G/SPLINES
algorithm developed by Rogers [46]. It has an advantage
over the conventional approach used for QSAR model
prediction, like it builds the model that has a higher
predictability and can address the problem that is not solved
by the standard regression method. It also has the capabilities
like generating multiple models and selecting multiple features
for model construction. It includes the higher order polynomial
and spline function where the main focus is on creation of
many nonlinear models. The initial models generated are
evaluated using the natural selection hypothesis. The automatic
method then after is applied to remove outliers. The GFA
method uses the LOF (lack of fit) score for measurement of
error in each QSAR model. Each model goes routinely under
evaluation test for fitness of model and the numbers of feature
required for constructing an accurate model. It also provides
checks for outlier and over-fitted data [47].
vi. Pattern Recognition
Pattern recognition is a value-defined method mainly
focused on the classification of data [24]. The basic difference
between the classical approach of QSAR and the pattern
recognition method is that it uses a large number of variables.
The relationships between large numbers of variables are
studied using the pattern recognition method like how much
diverse or closeness is present in it. The most commonly
employed methods of pattern recognition are cluster analysis,
Artificial Neural Network (ANN) and k-Nearest Neighbor
(k-NN) [24, 48, 49].
vii. Cluster Analysis
Cluster analysis is the basic method for classification of
data and also has been called as the statistical pattern
recognition method or the distance-based approach, where
data is clustered in so many groups according to the close
proximity between them. In this method, four key steps are
involved: generating key features of each chemical data set
and calculating similarity or diversity in data set, then using
various clustering programs cluster the data and finally one
representative is selected from each clustered class. The
similarity between data in each class is calculated using
similarity coefficient and each chemical data representative
Recent Advances in Multidimensional QSAR (4D-6D): A Critical Review
is noted using a binary set of descriptors. Most clustering
techniques are non-overlapping and this overlapping method
is divided into two classes: hierarchical and non-hierarchical
[50].
viii. Artificial Neural Networks (ANN)
Artificial neural networks (ANN) was developed by
Teuvo and Kohonen and is mostly used in the QSAR approach
because it is transparent and easily interpretable. An ANN is
a data analyzer and a data processer technique and works on
the function of biological nerve system. The architecture of
ANN is similar to that of a biological nerve system where
each neuron is connected to each other and each neuron is
artificial in nature. Here each neuron is a highly processing
unit connected to each other and it works in parallel, mostly
used to design parallel computational systems. A series of
layers arranged as a network on each other and each network
consists of nodes and edges. The first layer consists of the
input layer where it uses the input fed by the user, the second
one is the middle layer – also called the hidden layer – where
data analyzed in QSAR are mostly of independent variables
like property of molecular fragments and last layer is output
[51].
ix. k-Nearest Neighbor (k-NN)
k-Nearest Neighbor (k-NN) is one of the most simple and
exploited pattern recognition methods. Here, k is a small
positive integer and the method has an objective that it
classifies the object (i.e. chemical compound). The k-NN
utilizes the principle of Euclidean distance metric to classify
study data with close proximity. In the QSAR study, the average
majority is calculated by the voting neighbor in a similarity
index value to its molecular descriptors. The actual working
of k-NN follows the Euclidean distance metric and it is used
to calculate the similarity index between numbers of chemical
compound present in the dataset, i.e. training and unknown
entity [51]. This calculation will help determine the possible
value of integer kappa (k), the above values obtained will help
classify the unknown compound in the dataset dependent
upon average majority of the unknown compounds. The above-
mentioned technique is cross-validated with the highest
leave-one-out (LOO) cross-validated correlation coefficient
(r2) and (q2) [52].
C. LIMITATIONS OF 3D-QSAR
The 3D-QSAR is a novelistic approach as compared to
the 2D-QSAR but still facing some drawbacks like huge
number of chemical data (thousands of chemical structure)
cannot be handled by this approach and for this high-throughput
virtual screening method has been used [53]. Investigation of
the active conformation of flexible compounds in a study set
is critical followed by the specification for the molecular
alignment in constructing a 3D-QSAR model [54]. The
intermolecular interactions of receptors also need to be
studied because different types of interaction will take place
at different sites. These intermolecular interactions of the
molecules or receptors are called as interaction pharmacophore.
The topological descriptor studied in 3D-QSAR works on
the same connectivity principle as in 2D-QSAR. The 3D
orientation of ligands needs to be studied as it may affect the
rate of selection of correct bioactive conformation [55].
Mini-Reviews in Medicinal Chemistry, 2014, Vol. 14, No. 1 43
2D vs. 3D-QSAR
The primary goal of 3D-QSAR is to establish the
relationship between biological activity and spatial properties of
chemical compounds like steric, electrostatic and lipohilic.
The 3D-QSAR is mostly applied to series of chemical
compound to find out the molecular pharmacophoric features
in it by carrying out analysis and optimization of those ones
that can increase the biological activity [24]. The 3D-QSAR
studies are mostly focused on how change in 3D structural
features of chemical moiety will result in change in the
biological activity. It mostly provides information about the
structure activity relationship in the form of graphical form
for easy understanding, thus making it the most attractive
method [22]. The structurally diverse set of compounds is
easily studied for structure activity relationship as compared
to the 2D-QSAR traditional approach [17]. The prime
difference between 2D and 3D-QSAR is in the use of
statistically more robust methods for selection of molecular
descriptors like simple linear regression, multiple linear
regression (MLR), principle component analysis (PCA),
Principle component Regression (PCR), PLS analysis, GFA,
Cluster analysis, Artificial Neural Networks and k-Nearest
Neighbor method, which help in quantitative prediction of a
diverse set of 3D properties of chemical compounds [19].
0D- 3D QSAR
The simplest and easiest way to represent chemical
compound is molecular formula, simply is the constitutional
properties. Pérez-Garrido et al. [89] explained multiple linear
regressions by QSAR model of
- cyclodextrin (CD). The
aim and objective of study was to establish correlation
between CD binding constant and substituent changes in CD
structure. Free software package is used to study 0D to 3D-
QSAR called as DRAGOAN. The study of 233 chemical
compounds are done by calculating 1600 molecular descriptors
and further divided them in to 0D, 1D, 2D and 3D. The
separation between these descriptors is done by clustering
technique called as k-means clustering analysis. The efficient
variable in the procedure is selected by selection procedure
called as Genetic algorithm; the multiple QSAR models are
satisfying the internal predicative accuracy by cross validation.
The further study done in case of external data using genetic
simulation approach for cross validation of the data. This
will help in statistical predication of external data. There is
significant variation in case of many models (0D,1D and
2D), but there is good correlation between CD binding constant
and substituent changes in case of hydrophobic and steric
descriptors (3D).
4D-QSAR
The recent study has suggested that techniques used in
3D-QSAR like CoMFA had the same limitation in predictive
quality. To work out the above limitation there is a need to
improve the description or representation of molecules,
alignment of the compounds and statistics used in activity
predication [57-58]. To overcome these limitations a new
approach of QSAR (4D-QSAR) is evolved where modeling
statistics are improved, which helps in better predicative quality.
The recent advancement in QSAR developed two
approaches, namely receptor independent (RI-QSAR) and
44 Mini-Reviews in Medicinal Chemistry, 2014, Vol. 14, No. 1
receptor dependent (RD-QSAR) [59]. These approaches
have a number of steps that are involved, like the generation
of multiple conformation, alignment and consideration of
multiple sub-structure groups, are taken into consideration
[60]. The determination of free energy of binding is very
important in receptor-ligand interaction as it mainly corresponds
to the loss of free energy, also excluding of some solvent
molecules from the active site of receptors. These factors
significantly contribute to the measurement of binding affinity
between them [61]. All these activities in the active site of
receptor will lead to change in topology; this phenomenon is
commonly called as induced fit. The topological change will
also lead to change features like hydrophobic, hydrophilic,
electrostatic, dielectric or steric and solvent accessibility
[62]. The induced fit and flexibility the of receptor binding
pocket to an individual ligand topology are intensively studied
in multidimensional QSAR. All these multidimensional
properties predicted by the QSAR approach is quantifies
for all such parameters to sufficiently predict the QSAR
model.
The fourth dimension of QSAR analysis is also called
“ensemble sampling” [55]. This is new dimension to
quantitative structure activity relationship study mainly
focuses on some of the problems raised in the 3D-QSAR study.
4D-QSAR is as an extension of molecular shape analysis
(MSA) introduced by Hopkins et al. [62, 63]. They found
that the 4D-QSAR model was more robust and yielded a
more predicative model as compared to the conventional 3D-
QSAR approach like CoMFA. The main focus of this
approach is to the screen libraries of bioactive conformations
to check their structure activity relationship and the establishment
of fond relationship to biological activity. The principle
behind 4D-QSAR study is structure-based drug design (SBDD)
where issues like ligand conformational flexibility the multiple
alignment exploitation have been solved [55]. There are
several parameters in 4D-QSAR used in analysis like grid
cell size(s), molecular dynamic simulation of reference molecules
(R), temperature (T), size of initial ensemble sampling (Es),
number of alignments (Na) and numbers of descriptors in
initial basis set (Nd) [55, 62, 64-67]. As discussed above
there are two main elements.
A. RECEPTOR INDEPENDENT 4D-QSAR
Receptor independent 4D quantitative relationship study
has a significant impact in rational drug design. The
application of RI 4D-QSAR comes mostly in the picture,
when the researcher either wants to find pharmacophoric
features of the ligand molecules or to find the projected
changes in ligand structure [67]. The ultimate aim of RI 4D-
QSAR is to obtain maximum structural information after the
structure activity relationship study. The advantages of RI
over RD, it will design and construct Pharmacophoric
features for limited number of substituent, design and map
rational base for substituent placement on scaffold and designed
Pharmacophoric model can be used as an initial filter in
virtual screening. The successful implementation of RI 4D-
QSAR is done in studies like TMPKmt inhibitors and Isoniazid
Derivatives [67]. There are ten principal steps involved in RI
4D- QSAR.
Damale et al.
i. Initiation of Reference Grid for 3D Models of Training
Set
This is a foundation step in RI 4D-QSAR analogous to
CoMFA in 3D-QSAR where around 3D structure of training
set reference gird box is specified. This is one of the
parameter in RI 4D-QSAR study. In 4D-QSAR initial 3D
structure are starting point in conformational ensemble
sampling of the training set. The training set conformations
with minimum free energy and having common torsion angle
are selected. This also provides reference points in 4D-
QSAR analysis.
ii. Selection of Interaction Pharmacophore Elements
(IPE)
The each atom in each molecules are classified into five
to six different classes like, all atoms of the molecules
(IPE)a, polar atom of the molecules (IPE)p, non polar atom
of the molecules (IPE)n, hydrogen bond donor(IPE)hbd,
hydrogen bond acceptor(IPE)hba, user defined IPE types(IPE)x,
aromatic carbon and hydrogen. This classification helps to
analyze and understand different interactions involved in
each pharmacophoric site.
iii. Creation of Conformational Ensemble Profile (CEP)
The conformational ensemble sampling is done in training
dataset in study which helps in find out active conformation
in training data set. The molecular dynamic simulation (MDS)
is an advance approach routinely used to create ensemble for
each training set molecules. CEP uses Boltzmann sampling
techniques. The objective of this step is achieved by systematic
conformational search technique or stochastic conformational
search technique. Large number of conformers are explore and
correct conformation state is selected. As mentioned above,
Boltzmann sampling is commonly used because of list of
advantages like:
1) It is independent on sampling size.
2) Different starting state lead to produce same sample
distribution.
3) As different sampling scheme has used that will lead to
produce same state of optimized three dimensional
structures.
4) The average rate of change in energy with change in
state is almost zero.
iv. Selection of the Trail Alignment
The molecular alignment of training data set is major
problem in 4D-QSAR study and can be solve by rapidly
evaluating the trail alignment. The rapid evaluation of trail
alignment is done by searching and sampling operation
analogs to CEP. In general this is achieved by designing RI
4D-QSAR algorithms which help in alignment analysis by
decoupling of conformational analysis and further rapid analysis
of conformation to investigate the molecular descriptor on
molecular alignment. The CEP for each compound from
training data set is evaluated for molecular alignment and
this mainly corresponds to significance of 4D-QSAR model.
The molecular alignment produces unique models of every
Recent Advances in Multidimensional QSAR (4D-6D): A Critical Review
compound in gird box. This will result in development of
occupancy distribution for given CEP.
v. Construction of Grid Cell Occupancy Profile (GCOP)
and Calculation of Grid Cell Occupancy Descriptors
(GCOD)
The each conformation is placed in reference cubic
lattice reference grid cell and spacing of cell is as per trail
alignment. The GCOP is calculated for each compound based
on five to six different classes of interaction pharmacophore
elements. These IPEs used to do trail alignment of 4D-
QSAR descriptors. The cell occupancy for each grid cell is
taken into consideration after alignment of each IPEs atom in
a grid cell it result in formation of unique set of IPEs. This
set of IPEs for each atom in QSAR called as grid cell
occupancy descriptors, GCODs. Three grid cell occupancy is
calculated for each IPEs by taking in accounts of absolute
occupancy (Ao), Cartesian coordinate of grid cell where i, j,
k defines dimension of grid cell and time t for ensemble
generation for each IPEs atoms. The joint occupancy (Jo)
measurement is an important task and effectively done by
putting reference compounds (R) into gird cell. And lastly,
self-occupancy is studied it generally relative to grid cell
occupancy of reference compounds (R). There is no official
guideline regarding which occupancy descriptor regarding
which should be included and which should be left from
particular study. The reference compounds are really helpful
or will lead to generation of biasness in 4D-QSAR model.
The biasness may be helpful in generation of 4D-QSAR
model towards template based properties. The reference
compounds selected for study so that highly potent member
of series get selected and that result in highly influence with
activity potent features. From numbers of study it is suggested
that use of joint occupancy descriptor are used when small
group of compound present in study set, where as absolute
occupancy descriptors useful in case of large number of
compounds.
vi. PLS Analysis to Reduce Number of GCODs Against
the Biological Activity Measures
There are several reasons, because of which large number
of grid cell occupancy descriptors are generated such as a
result of enormous rigorous trail alignment, numbers of grid
cell, five to six IPEs and three different possible occupancy.
Data reduction step in 4D-QSAR is similar to CoMFA with
slight difference where complete set of grid cell occupancy
descriptors are included into study. The all atoms IPE CEPs
generated in grid cell, and location of molecular shape with
respect to the IPE is calculated using plot of Boltzmann
average. In this plot joint occupancy (Jo) measurement is
done by mapping grid cell location into a single location
index m this plot also known as molecular shape spectrum
(MSS). The difference in biological activity of two compounds
is distinguished by difference in their molecular shape
spectrum. In this step location of such IPE CEPs is tried to
identify in the grid cell. The MSS may be dependent on
several things like size of grid cell, coordinate positioning of
the compound and can be evaluated by shifting the coordinate
of compounds or by changing the cell size. The PLS is used
to perform regression analysis to remove unnecessary
GCODs by establishing the relationship between experiential
Mini-Reviews in Medicinal Chemistry, 2014, Vol. 14, No. 1 45
biological activity and occupancy value of GCODs. The
values obtain from PLS regression related quantitatively
with 4D-QSAR model, by giving specific weight age to each
GCODs and quantitative relationship between small groups
of selected GCOD represented by graphical mode. In general
small groups (<15) of GCODs are selected for 4D-QSAR
studies which are significant in 4D-QSAR model.
vii. 4D-QSAR Model Building, Optimization, Comparison
and Evaluation
The highly weighted grid cell occupancy descriptors are
selected; further, genetics algorithm (GA) and genetic function
approximation (GFA) are used for RI-4D-QSAR model
building, optimization, comparison and evaluation. These
highly weighted set of GCODs generated in pervious step by
trail alignment used in model building by GA analysis. The
basic requirement of this algorithm that only linear terms are
used by multiple linear regressions. The model optimization
is done after analysis of resultant 4D-QSAR models, where
several diagnostic operations included in the study like
crossover, linear crossover to relate GCODs and biological
activity. Finally, model comparison and evaluation are
performed using techniques like Leave one out-Correlation
coefficient, Cross correlation, Correlation coefficient, Lack
of Fit.
viii. Retrial of Trail Alignment, Creation of IPE CEPs
and Selection of GCODs Unless Included for GA
Analysis
Based on trail alignment, a model is constructed and
evaluated with composite set of 4D-QSAR models constructed
on repetition of step iv to vii. It also can be achieved if trail
alignments are sampled. Once desire set of trail alignments
included into construction of 4D-QSAR model, proper
optimization, comparison and evaluation of all models are
done.
ix. Identification of “Best” 4D-QSAR Model With
Respect to Trail Alignment
Detail assessment and evaluation of 4D-QSAR models is
constructed in set of QSAR population. The basic objective
of this step to find “Best” optimized 4D-QSAR model. The1
specific best trail alignment is selected on the basis of highest
goodness of fit of regression coefficient and q2. Generally, to
choose best trail alignment with high q2 a cross-correlation
matrix of the residuals in error is done in case of pair of top
4D-QSAR model. This is done generously to know similar
and distinctive structure activity relationship to find unique
best 4D-QSAR model present in the study.
x. Proposing the Hypothesis about Active Ligands
Conformations
The aim of this step is to find or identify active state of
conformers generated for each compound and sampled for
conformational search which is belonging to lowest energy
level E (Global minima) of CEP. These all selected lowest
energy conformers are evaluated using q2 for best 4D-QSAR
model. Also conformation with maximum Gird cell occupancy
or consistent with lowest energy conformation or after
molecular dynamic simulation ensemble sampling of GCOD
are used for evaluation of activity of 4D-QSAR model. The
46 Mini-Reviews in Medicinal Chemistry, 2014, Vol. 14, No. 1
hypothesis is made about predication of conformation with
lowest energy which is “high at activity”. The hypothesized
highest activity conformation is used as template structure
for structure based drug design. The use of molecular
geometry of template with receptor ligand interactions is best
source for structure based drug design.
B. RECEPTOR DEPENDENT 4D-QSAR
Receptor-dependent 4D-QSAR is the new approach
in QSAR where experimental techniques like X-ray
crystallography, NMR spectroscopy and comparative
modeling/Homology modeling are used to determine 3D
structures of macromolecules. The database such as PDB,
SCOP and CATH are depository for it. The 3D structure is
determined, the binding site for the ligand is predicted, and it
allows knowing the binding and alignment modes of ligands.
The basic aim of the RD 4D-QSAR study is to map the
ligand-receptor interaction mode. The binding mode
information from such series of ligands allows one to
construct site occupancy- weighted 3D pharmacophore
models. According to the binding interaction weight of the
pharmacophore is assigned. The relative occupancy of
pharmacophore is evaluated thermodynamically by accessing
conformational state of the receptor ligand complex. The
complex of receptor ligand is analyzed as stated above for
Fig. (2). Methodology of RD 4D-QSAR analysis.
Damale et al.
binding mode and alignment; there are a number of methods
used to study it like gird cell based hot spot analysis (GCB-
HSA), ensemble simultaneous search (ESS) and composite
crystal-field analysis (CC-FA). In SBDD two are the best
approaches to find novel ligands like virtual screening where
ligand shape and molecular features play an important role in
searching novelty. Another approach is de novo approach
where molecular interaction between receptor-ligand is
significant in designing of novel inhibitors. SBDD has four
common limitations in order to find novel hits:
a) Ligands’ conformational flexibility is not taken into
consideration, only single conformation is used, which
might create ambiguity. The above problem is because
of free ligand conformation and which is different from
the actual bound conformation in the active site. The
multiple conformations in the form of ensembles are
considered as that of single conformation in order to
address conformational flexibility.
b) The bonded and non-bonded interaction between the
receptor and ligand may change the conformation of
active site. We mostly called it the induced fit effect,
which may play a role in the recognition of the novel
ligand. This has not been consider in most of the SBDD
studies and called it as rigid fit effect. In recent studies
Recent Advances in Multidimensional QSAR (4D-6D): A Critical Review
multiple protein conformations (MPS) are taken in the
form of ensemble docking to find the induced fit effect
in the binding mode.
c) The numbers of scoring function are used, which calculate
the free energy of binding between the receptor and the
ligand and to do it numbers of force fields are used. Force
fields are mostly calculated for non-bonded interaction
receptor and ligand, but till date no scoring function has
been designed, which can calculate the correct binding
affinity.
d) Solvation terms like desolvation and resolvation are not
considered generally and it might affect the ligand receptor
binding interactions. These solvation effects have a
direct impact on binding strength of receptor and ligand,
and neglecting of these interactions will lead to wrong
estimation of the biological activity of ligand moiety.
Generally solvation effect will lead to change in geometry
and free energy of the complex.
The specialized design of RD 4D-QSAR will focus on
such problem arising in SBDD, which can be reduced to the
lowest level and the proper quantitative relation can be
established between features of ligand molecule and biological
activity [68]. Basic methodology and analysis of RD 4D-
QSAR is shown in Fig. 2.
The numbers of studies are carried out in receptor-
dependent 4D quantitative relationships like glucose analogue
inhibitors [68], enoyl-acp reductase inhibitors [65], 4-
Hydroxy-5, 6-dihydropyrones as Inhibitor of HIV-1 Protease
[85-86], p38-mitogen-activated protein kinase [87] and 14-
-
lanosterol demethylase [88].
C. LQTA 4D-QSAR
It is a new conception in 4D-QSAR study, Laborato´rio
de Quimiometria Teo´rica Aplicada (LQTA) where
conformational flexibility is mostly studied [69]. In routine
4D-QSAR study IPE and GCODs are calculated to predict
the biological activity of chemical moiety. In LQTA 4D-
QSAR numbers of conformations are generated and after
that conformations are optimized to calculate 3D descriptors.
The basic methodology of LQTA 4D-QSAR, is the same as
that of RI 4D-QSAR, where the numbers of conformations
are generated and their interaction pharmacophore energies
are calculated in the grid cell. The number of molecular
dynamics and molecular simulation packages are used to
generate ensembles. The molecular simulation and MD
studies are carried out in the presence of solvent interaction
which involves a better understanding of natural conditions
[69, 70]. The basic methodology of LQTA 4D-QSAR is
divided into four steps and is explained in Fig. 3.
i. Design or Retrieval of Ligands
The molecular structures of ligands are sketched with
various molecular modeling packages and their after-energy
is minimized and converted to 3D conformations using
suitable force fields. Molecular dynamic programs like
GROMACS or online servers like DYNAPOCKET are useful
in generation of topology and coordinates for ligand atoms
[70, 71].
Mini-Reviews in Medicinal Chemistry, 2014, Vol. 14, No. 1 47
ii. Generation of Ensembles
The number of molecular dynamics and molecular
simulations packages used most commonly GROMACS
because of its open access and it is fast in computing
molecular ensembles using numbers of different force fields.
The .gro is an output of input file and it is an extension of
GROMACS package as a trajectory file in which coordinates
of ensembles are stored. In .top or .itp file generated as input
of .gro file, which includes topology and atomic energy in
the form of Columbic and Van der Waals energy terms. The
output of .gro file and .top/.itp file is used as input for
calculating the 3D interaction energy descriptors in the grid
cell. To calculate this interaction energy uniformly, the grid
is defined, which occupies all the conformations. The
interaction at each point in the grid is calculated by placing a
probe at specific junctions of the grid [70-71].
iii. Computation of 3D Properties
Generally, probes placed around grids are ions, cations or
a functional group of positive or negative charge used for
computation of energy at regular spacing in 3D grid cells. As
defined, earlier energy in the form of Columbic and Van der
Waals is calculated for each atoms of CEP using various
force fields. Both Columbic and Van der Waals energy are
calculated for ‘n’ number of atom and the mean of this
energy value is useful to calculate all copies of ligands in
each grid point [70, 71].
iv. Correlation Descriptors between Biological Activities
The output of computation of 3D properties is at each
grid point where columns contain information about energy
for each atom in regular spacing 3D grid cell which contains
information about descriptors. In the same way, rows define
sets of chemical compounds under study in the grid cell. The
simple matrix is defined containing values of columns and
rows to select relevant molecular descriptors in the study.
The multivariate regression approach (PLS/PCR) used to
construct the QSAR model for relationship between
independent variable “biological activities” with dependent
variable 3D properties at each grid point, which is defined as
“descriptors” [70, 71].
D. SOM 4D-QSAR
The exclusive focus of 4D-QSAR is to model the 3D
properties of chemical compounds, and to construct and
analyze conformational profile of receptor ligands. The self-
organizing map (SOM) was the unsupervised Machine
Learning type and used to classify the data according to the
similarity in it. It is a basic type of ANN developed by Teuvo
and Kohonen and it is mostly used in the QSAR approach
because it is transparent and easily interpretable. It is mostly
used for classification and to test the toxicity of chemical
compounds. In the design of the SOM/KN network you will
find 2D grid of connected-neuron network and a layer of
multidimensional vectors, each dimension of vector representing
a descriptor. The system of neuron learn in two steps: one is
election of a similar neuron (winning) and the other is where
the weight of winner neuron is modified by vectors so that
neighbor neurons get similar values and self-organizing map
is set up. After all the input is offered to the network, and the
48 Mini-Reviews in Medicinal Chemistry, 2014, Vol. 14, No. 1
Fig. (3). Methodology of LQTA 4D-QSAR analysis.
learning process is over, network, became stable and each
layer of vector represents the value of each descriptor and it
tries to preserve that information [51]. As we know the
QSAR study can include many descriptors (logP, mol.wt,
kier and Hall indices) and SOM/KN does not have any
problem to include them in the study; hence, in 3D-QSAR it
is used mostly when molecular shape, spectra or any other
encoding 3D features are used. The statistical result of the
SOM/KN model is compared with other methods like the
linear or MLR model. In general as discussed above, multiple
conformations of ligands are developed in the 4D-QSAR
model. The method is suited for experiments where active
bound conformation is searched, taking into account
conformation flexibility. The basic methodology of SOM
4D-QSAR is divided is into six steps [72, 73].
i. 3D Model Building and Ensemble Searching
The initiation of SOM 4D-QSAR begins with generation
of 3D conformation of selected ligands in training set.
Ligands 3D structure are minimized and active conformation
are searched in ensemble sampling.
ii. Trail Alignment or Superposition
The selected active conformations of ligands are subjected
for trail alignment or superimposition. The procedure worked
on the basis of active conformer and selecting at least three
atoms for superposition in the alignment.
iii. Finding of Interaction Pharmacophore Elements
(IPE)
The aim of this is step to find and select groups of atoms
that play an important role in interaction by placing selected
conformer into grid cell and their fragmenting ligand. The
apparent selection of interaction groups like aliphatic,
aromatic, hydrogen bond donor, hydrogen bond acceptor and
polar and non-polar charge groups is done by placing probe
at regular spaces of 3D gird cell.
Damale et al.
iv. Creation of Conformational Ensemble Profile (CEP)
The training set selected in step1 after energy minimization
are subjected for molecular dynamics studies and molecular
ensembles are created for each ligand molecules are used
for conformational ensemble profile. The molecular
dynamic study also helps in comparative analysis of ligand
conformations. Semi empirical method such as AM1 method
is used to calculate partial charge of compounds.
v. Construction of Comparative 2D-SOM Map
At this step 2D self organization maps are constructed
based on CEP for each ligand after calculating Cartesian
coordinates and partial charges. At the training stage values
of each ligand are provided as input data by means of Grid
cell Occupancy Profile (GCOP) and partial charges to neurons
to get Occupancy Profile maps or partial charges maps.
vi. Data Reduction and Model Validation
The terminal and final step in SOM 4D-QSAR where
specific occupancy and partial charge groups are selected for
PLS analysis and variables are eliminated. In 4D-QSAR,
relationships are built up based on leave one out (LOO) and
cross validation (CV) procedure in association with iterative
variable elimination (IVE-PLS). Model validation is done by
cross validating QSAR model with external test set data by
measuring predicative ability and to do so variety of training
and test set are sampled and monitored by Stochastic Model
Validation (SMV) scheme.
4D Vs 5D-QSAR
The comparison of 4D-QSAR with 5D-QSAR helps
measure the performance of these multidimensional QSAR
approaches in drug discovery and development. The
performance of 5D-QSAR is evaluated using the analyzing
residual test (|Gpred° - Gexp°|) [74].
Recent Advances in Multidimensional QSAR (4D-6D): A Critical Review Mini-Reviews in Medicinal Chemistry, 2014, Vol. 14, No. 1 49

5D-QSAR donor, acceptor at the complementary directed group at

ligand molecule and it also includes hydrogen bond Flip
The Quantitative Structure Activity relationship is the
flop. The atomistic or proxy receptor model is created using
most well-established research field of computational chemistry
the Quasar concept, which was introduced by Angelo Vedani
dealing with building computational models of chemical
et al. (Fig. 5). The receptor surface model gives an idea
compounds and correlating it with biological activity. The about proxy or hypothetical receptor binding site, which
basic ideology behind the 3D or 4D-QSAR models is that
mapped into 3D features into the properties that can help in
compounds with different biological activities are mostly
projecting them on the receptor surface. The nature, shape,
because of either a different molecular field or because of
size and location of these surface and 3D features will help
correct bioactive conformations. The hypothetical virtual
in understanding the role like steric, electrostatic or bulk
models built are mostly used to predict binding affinity and
nature of a mapped binding surface. There are several allied
the pharmacokinetic and toxic properties of chemical properties of binding receptor like hydrophobicity, hydrogen
compounds. The recently developed approach of Quantitative
bond donor, hydrogen bond acceptor and partial charges.
Structure Activity relationship is used to address receptor
The evaluation of atomistic or proxy receptor or surface
flexibility. The inherent flexibility of the receptor has often
receptor is checked by validating two properties of surface
been overlooked in drug design, despite recent accounts of its
receptor, which are involved in the simulation of receptor
importance in the design of several inhibitors. The receptor
atom like induced fit and H-bond flip-flop. Momentary
ligand is the multifaceted object where ligand binds to the hydroxyl amino acids Ser, Thr, Tyr, Cys, His, Asn and Gln
receptor to a lowest energy conformation state and to do so
present in the binding surface play an important role in
the receptor structure will distort to engulf the ligand
induced fit and H-bond flip-flop to the ligand molecule.
molecule. To understand the details about the distorted state
While building the atomistic model the main aim is to
of the receptor as a result of formation of binding complex
establish an average stimulated model that interacts with a
two states of receptors are considered, i.e. Apo (unbound)
series of ligand molecules. The multiple representation of ligand
and Holo (Bound) (Fig. 4). topology to study conformation, isosteriomer, protonation and
The phenomenon of receptor flexibility and the orientation is generally called the new dimension of 4D-
consequent actions are generally represented in the form of QSAR as it can be represented in multiple induced fit and
energy-level transitions. The receptor flexibility will follow referred as the new revolution in QSAR called as 5D-QSAR.
several incidents like receptor refolding and formation of
The multiple representations are used as ensembles in
compact hydrogen units (CHUs). In receptor ligand binding,
4D and 5D-QSAR study, where molecular simulation and
several forces play a role to determine the selective or Boltzmann weighted selection criterion for bioactive
peculiar binding pose, like hydrogen bonding, covalent metal
conformation are selected as genetically evolved from a
bond and electrostatic bond [56]. The binding interactions
reservoir of conformation. In the Quasar concept local
are mostly studied in molecular docking where only one
induced fit in atomistic receptor is simulated by introducing
ligand molecule will bind to receptor, but in Quantitative
“pharmacophore equilibration” mapping ligand in the
Structure Activity Relationship study several aligned series
training set as “Inner” and “Mean” envelope. The inner
of ligand molecules are considered to evaluate biological envelope is created by mapping all training ligand sets at a
activity [75]. The simultaneous binding of receptor to ligand
Van der Waals distance whereas the inner core of the envelope
is studied as atomistic or proxy receptor. The factual
is created by tightly accumulating and accommodating each
flexibility of receptor conformation is created in atomistic or
ligand molecule. The mapping of “Inner” and “Mean” envelope
proxy receptor by introducing flexibility on hydrogen bond

Fig. (4). (a) Explicit simulation of induced-protein fit in 5D-QSAR; (b) Explicit simulation of induced fit by a dual-shell representation of
the three-dimensional binding-site model [57].
50 Mini-Reviews in Medicinal Chemistry, 2014, Vol. 14, No. 1
Fig. (5). Quasi-atomistic receptor model for the receptor system generated by the software Quasar [76].
design on basic approaches is first performed isotropically
(linearly), second anisotropically (steric, electric, H-bond or
lipophilicity-potential scaled) and third through energy
minimization. As discussed above, the fifth dimension induced
fit model cannot be created without considering factual
receptor; to do, a so number of simulations and induced fit
hypothesis are considered to create a factual receptor. To
construct a fifth dimension model several techniques have
been used like building it on the modus operandi of the mean
envelope. The Quasar concept used in building local induced
fit in atomistic receptor is created by a changeable degree of
freedom from 0 to 1 degree where 0 indicates no mobility in
receptor and 1 as the perfect local induced fit model. The
perfect atomistic receptor model is created, which allows
generating the perfect receptor binding surface where 3D
receptor models are created choosing peculiar surface
properties. The construction of a 3D pharmacophoric model
will help in allowing receptor surface and ligand to adapt to
each other conformationally as well as hydrogen bond mediated
flip-flop of hydroxyl-containing amino acid towards well-
adopted structure of ligand molecules. The set of these atomistic
receptor surfaces are created using genetic algorithm and
again are validated using cross-validation protocols. In the
Quasar approach with site directed hydrogen flip-flop bonding,
the solvation term also has been studied [76-80].
A. METHODOLOGY OF CONSTRUCTION IN QUASAR
i. Building of Receptors “Inner” and “Mean” Envelope
Local induced fit in atomistic receptor simulated model is
constructed for each training ligand set by creating inner
envelope of van der Waals distance at topology of each training
Damale et al.
and test set. The building of receptors inner envelope is
achieved by mapping significant three dimensional features.
The correct protocol for this is firstly to map surface on brief
and make the inner core envelope and then after snugly
accommodate all the ligand training set. This will create
accurate induced fit three dimensional models by firstly
isotropically (linearly), secondly anisotropically (Steric, electric,
H-bond, or lipophilicity-potential scaled) and thirdly through
energy minimization. The dimensionality induce fit is
calculated by measuring root mean square deviation from
mean (0.4-2.5 Å). The free energy association between
receptor-ligands is calculated by means of inner core envelope
(0.2-6.0 kcal/mol).
ii. Generation of an Initial Set of These Atomistic
Receptor Surfaces of Parent Structures
The significant three dimensional properties of atomistic
receptor surface are randomly distributed. The numbers of
points of receptor surface are calculated using atomistic
populated properties, minimum distance between two populated
properties as default are set as 2.4 Å. These properties are
sense as most saturated functional groups of most potent
ligand molecule of series of ligand molecules. The precise
and more potent ligand molecules are estimated using
intrinsic affinity towards receptor surface. The position and
geometry of receptor surface will remain still throughout the
simulation. The vector support method used for identification of
binding cavity present on receptor surface which will yield a
best position for ligand functional groups to form non
covalent bond with (directional H bond) a receptor surface.
The above method followed to generate ‘n’ number of
atomistic receptor surfaces of parent structures. The solvation
Recent Advances in Multidimensional QSAR (4D-6D): A Critical Review
effect of solvent also have to study on receptor binding
pocket because it mainly as a part of envelope to represent
solvent accessible area. This region open as void and
hydrophobic in nature which is motionless static dynamically.
iii. Genetic Evolution of Set of Atomistic Receptor
Surfaces of Parent Structures
Genetic algorithm is the class of model optimization
method Darwinian evolution. Genetic algorithm is widely
used method in the field of computational chemistry and
chemoinformatics and applied mostly in protein ligand
docking or Quantitative structure activity relationship study.
In the assumption of genetic algorithm study creation
random of ‘n’ number of sample population by either cross
over or mutational approach and after that finally evaluate
them to find best among the sample population. The
evolution study depends upon finding fitness function and
based on fitness function sample population are ranked. In
cross over study, parents selected for genetic study are best
fit for the cross over study and cross validatory q2 which
indicate higher or lower value indicating kind of group of
individual selected for study. Then after cross probability q 2
value is calculated to measure fitness of produced population
ranging from 0-1. The lock of fit is calculated to measure the
different properties of parent structure with in the population
(Predicated and experimental) in study to validate induced fit
by considering three penalties like protonation state,
selectivity of ensembles and property difference between the
model.
LoF =rms [G°pred - G°exp]/{1.0 - (ppart + pdiff +
psele)/3.0}
iv. Measurement of Free Energy of Binding
As mentioned above in measurement of free energy of
binding between ligand and receptor both solvation energy
and entropy value are taken into consideration.
Ebdg ~ Elig_recy - TSbdg - Gsolv, lig + Eint, lig + E ind.
fit, lig
The solvation term mentioned in above equation is
necessary to address change in internal energy of binding of
receptor surrogate, the maximum internal energy of ligand
observed when appropriate accumulation of ligand by
receptor molecule where optimal ligand receptor interaction
observed. The solvation energy of ligand molecules in
receptor structure is accurately mentioned and explained by
Blaney’s approximation where he stated that all ligands are
buried into receptor surface with equal propensity. The
explanation to Blaney’s approximation is given with all
complexes of receptor ligands carries equal solvation energy
[81]. The ligand which is exposed differently to receptor
molecule with different binding fraction of binding site is
exposed to it, so correct portion of binding site exposed
defining is important. The interaction energy between receptor
and ligand calculation is important to calculate interaction
energy calculated by directional force fields (Vedani and
Huhta, 1990; Vedani et al., 1995). The free energy of ligand
binding and predication free energy (Gpre) are calculated by
calculating mean of each by linear regression of training set.
Gpre =|a|. Ebinding + b
Mini-Reviews in Medicinal Chemistry, 2014, Vol. 14, No. 1 51
The inherent slope and intercept of this equation to a
receptor model in study is used to predict binding energy of
compounds included into study which is other than training
set.
B. ANALYSIS OF RECEPTOR MODEL FAMILY
The receptor used in study is evaluated and validated
using external data set and criteria for evaluation is predication
of model receptor by predicting relative free energy of binding.
Other stringent criteria are set to evaluate model like cross-
validated q2 value and lack-of-fit [46]. Along with these test
uniformity distribution of envelope test is calculated like
SAS or hydrophobic pocket. The method used to select
diversified training compounds from available biological
data set in study ‘minimum distance’ method work to predict
true biological values. The algorithm of ‘minimum distance’
is developed with aim to select most diversified compounds
from set of biological data set in study. The minimum
distances between two compounds are calculated by using
weighed function such as electrostatic and van der Waals
interaction determined by using at common point of interaction
between them. The ability of this algorithm to predict true
biological value helps in selection of most potent compound
from dissimilar biological data set which later on can be used
as training set in QSAR study.
Local induced fit in QSAR model is considered in Quasar
technology and ensemble induced fit hypothesis is evaluated
to minimize biasness. In recent methodology some modification
are done to consider adaptation mechanism. 1) Linear mode,
which scale from 0.0 to 1.0 where 0 indicated no induced fit
where as 1.0 indicate maximum topological adaptation in
induced fit. In next three step i.e. 2-4 steric, electrostatic, and
H-bond field adaptation are considered. In step 5, energy
minimization based on steric potential and in 6th step, a
particular adaptation in topology in proportional to lipophilicity
potential of the molecule. The induced fit methodology adopted
are proportional to the steric, electrostatic, H-bond field and
lipophilicity potential which is directionally acting on mean
envelope of the model. The above step is followed by
constrained energy minimization to make definite separation
between neighboring points in linear gird. The linear mode
used for measurement of local induced fit behaves isotropically
and dependent on molecular properties such as shape, steric
potential, electrostatic potential, and hydrogen bond donor or
acceptor property or to lipohilic potential which yield an
isotropic induced fit model (Fig. 6). The genuine parents
induced model structure selected for study is evaluated using
lack of fit method the model with lowest LOF value are selected
for study.
6D-QSAR
The new dimension added to the QSAR study improves
the QSAR analysis. The additional dimension is included in
the QSAR study to consider solvation function [82]. This is
an extension of the Quasar technology, where using this new
dimension we allocate consideration of simulations for different
solvation models [83]. The solvation terminal (solute and
solvent) conceptualization is very important because here we
study their importance in non-covalent interaction between
ligand and receptor when they combine.
52 Mini-Reviews in Medicinal Chemistry, 2014, Vol. 14, No. 1 Damale et al.

Fig. (6). Stereo view of the envelope selection (induced fit hypotheses) [78].

The detailed concept of simulations solvation has been The result of these studies is also cross-validated using
explained over here by either implicitly or explicitly mapping experimental value.
the features of receptor-ligand like surface area (size and
3D to 6D- QSAR
shape) and solvation properties using genetic algorithms.
The solvation terminology used is either ligand desolvation Structurally Diverse 106 Ligands of Estrogen Receptor
or solvent stripping, which is directly measured in case are selected for study, the ligand molecules are divided into
different surrogate model families are used in measurement test (18) and training set (88). Initially three dimensional
of binding affinity. These surrogated model families of true structure of ligand molecules are energetically optimized
receptor binding pocket comprises features like hydrogen using force field like AMBER using Macro- Model software.
bond donor, hydrogen acceptor and hydrophobic and Further in study atomic charges and solvation energy is
hydrophilic. The result of measuring the binding affinity of calculated using AMSOL program. The numbers of conformer
surrogated model family will give us an idea about the are generated for each ligand molecules (4D) using Quasar
solvent’s accessible area. As mentioned above, features of tool and least energy conformer is retained in study. The 5D
receptor-ligand complex like SAA and solvation properties model is simultaneous evaluation of different induced-fit
are weighted and these are evolved through the intervals of scenarios very well suited for study of induced fit. And finally it
genetic simulation. The principles used in 4D- and 5D-QSAR is studied for different solvation scenarios. The advantage of
were 3D structures, which are generated and simulated using each of QSAR approach over other is efficiently shown by
moderate evolutionary pressure. The inherent characteristics comparing values of cross- validated and predicative r2 [84]
of ligand molecules are screen unbiasedly using receptor (Table 2).
properties like hydrophobic properties, characteristics of
binding pocket and SAA-called the receptor QSAR-based
receptor modeling. The compound included in the study Table 2. Comparison of predicative ability of 3D-6D QSAR
comprises both training and test set and as defined above a model.
surrogate model family of receptor is used in 6D- QSAR.
The surrogate model family has true biological activity the
QSAR Model Cross Validated r2 Predicative r2
model selected in the study and are evolved under the genetic
algorithms [84].
3D- QSAR 0.821 0.563
The Quasar-simulated model used in the study is evolved
4D- QSAR 0.810 0.788
and both cross-validation and predicative correlation value is
calculated to predict biological activity. The biological activity 5D- QSAR 0.872 0.790
of training and test compound is tested using characteristic
properties of true receptor in the binding pocket and true 6D- QSAR 0.903 0.885
positives are well selected by the receptor surrogated family.
Recent Advances in Multidimensional QSAR (4D-6D): A Critical Review
CONCLUSIONS
QSAR is the most reliable computational technique used
for decades for better insight on substituent’s physicochemical
property and biological activity. Number of developments
has been taken and different constitutional descriptors have
been explored. Advancements have been taken place
considering the limitations of previous one. After the
introduction of 3D-QSAR different advanced tools like
COMFA, COMSA, WHIM etc. extensively assist to study
multiple 3D descriptors of a chemical compounds establishing
correlation between structure and biological activity. More
advanced QSAR approaches like 4D, 5D and 6D-QSAR
have been evolved to overcome the limitations of 3D-QSAR.
Large number of reports appears recently for 4D-QSAR
studies of penicillin analogs which exploit Hopfinger’s
4D-QSAR schemes. There are some reports on recent
advancements like LQTA-QSAR approach. 5D-QSAR
studies are extensively described by tools like Biographics
Laboratory 3R, Quasar and Raptor. To consider the salvation
function, a new dimension has been originated known as 6D-
QSAR where we allocate simulations for different solvation
models. In this model, non-covalent interactions between
ligand and receptor are studied. Considering some recent
reports of novel approaches multidimensional QSAR might
serve as an important tool in drug discovery.
CONFLICT OF INTEREST
The authors confirm that this article content has no
conflicts of interest.
ACKNOLEDGEMENTS
The authors are thankful to the Mrs. Fatima Rafiq Zakaria
Chairman Maulana Azad Educational Trust Aurangabad,
Mahatma Gandhi Mission Trust Aurangabad and Dr. M.H.G.
Dehghan, Principal, Y.B. Chavan College of Pharmacy,
Dr. Rafiq Zakaria Campus, Aurangabad 431 001 (M.S.) for
constant support.
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Received: September 13, 2013 Revised: October 29, 2013 Accepted: December 01, 2013

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PMID: 24195665