GERF Bulletin of Biosciences 2010, 1(1): 37-40

Review Article

Insilco QSAR Modeling and Drug Development Process

Pooja Mishra1, Vijay Tripathi1, Brijesh Singh Yadav2*

1
Center of Bioinformatics, University of Allahabad, Allahabad, India
2
*Indian Veterinary Research Institute, Izatnagar, Bareilly, U.P., India

Abstract
In this paper we focused on in silico QSAR (Quantitative structure-activity relationship) modeling is one of the well-
developed areas in drug development through computational chemistry. Similar molecules with just a slight variation in
their structure can have quit different biological activity. This kind of relationship between molecular structure &
change in biological activity is center of focus for QSAR Modeling. QSAR are based on a comparison between some type
of activity & the chemical structure or physicochemical properties of a series of chemical.Quantitative structure-
activity relationship (QSAR) is the process by which chemical structure is quantitatively correlated with a well defined
process, such as biological activity or chemical reactivity. Activity = f (physiochemical properties and/or structural
properties). There is a wide variety of descriptors for use in QSAR studies. Actually descriptors are biological property
that represents in mathematical form. The group or subset of these descriptors is potentially useful for predicting
ADME/Tox properties, & describe the arrangement of a pharmaceutical compound without organisms. Here ADME is an
acronyms in pharmacokinetics & pharmacology for absorption, distribution, metabolism & excretion, this is the very
important step in drug designing is prediction of ADME property of any compound. It is useful to predict toxicity of
particular compounds. This article also reviews the current achievements in the field of QSAR modeling and their
impact on modern drug discovery processes. The applications of QSAR modeling in drug discovery, such as compound
selection, virtual library generation, virtual high throughput screening, HTS data mining, and in-silico ADMET are
discussed. We have also presented a quantitative structure–human intestinal absorption relationship using Regression
analysis through Tsar.
Keywords: Quantitative structure-activity relationship (QSAR), ADME, Descriptors, Clustering, Regression, TSAR

Introduction these computationally screened virtual libraries can then be

Drug is a complex set of molecules. It is not distributed in all
over body by complex form, so after being absorbed (orally
or by other route). It should be broken up to its in simplest
form & after that it can be distributed to all over body by
blood. After absorption & distribution the remaining waste
part of drug will excreted in body. Historically, drug absorp-
tion, distribution, metabolism, excretion, and toxicity
(ADMET) studies in animal models were performed after a
lead compound was identified. Now, pharmaceutical compa-
nies are employing higher-throughput, in vitro assays to
evaluate the ADMET characteristics of potential leads at
earlier stages of development (Jun Xu, 2002). This is done in
order to eliminate candidates as early as possible, thus avoid-
ing costs, which would have been expended on chemical
synthesis and biological testing. Scientists are developing
computational methods to select only compounds with rea-
sonable ADMET properties for screening. Molecules from
Corresponding Author: brijeshbioinfo@gmail.com
synthesized for high-throughput biological activity screen-
ing. As the predictive ability of ADME/Tox software improves,
and as pharmaceutical companies incorporate computational
prediction methods into their R&D programs, the drug dis-
covery process will move from a screening-based to a knowl-
edge-based paradigm. In silico QSAR modeling, feature se-
lection are used, this feature selections is used to reduce the
number of descriptors per compounds. Successful data min-
ing depends on good descriptor selection. If molecules are
represented by improper descriptors, they will not lead to
reasonable predictions. Correct descriptor selections rely
on understanding the computational problem that one is
trying to solve.
Correlation analysis and relevant analysis
approaches can help with this understanding. The criteria
used for selecting descriptors should be: the selected
descriptors should be bio-activity related (requiring
correlation analysis), the selected descriptors should be
informative (should have diversified value distributions),
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GERF Bulletin of Biosciences 2010, 1(1): 37-40
the selected descriptors should be independent of each other
(if two descriptors are correlated to each other, related prop-
erty will be unfairly biased), the selected descriptors should
be simple to extract, easy to explain to a chemist, invariant to
irrelevant transformations, insensitive to noise, and efficient
to discriminate patterns in different categories (specificity).
After comparing performance and predictability in high
throughput data mining, researchers from multiple groups
have consistently.
Computational Methods for the QSAR Modeling
Genetic Algorithm (GA)
Genetic algorithm is optimizing algorithm used in find true
or approximate solutions to optimization & search problems.
GA is categorized as global search heuristic. General
application of GA: Topology optimizations, Genetic training
algorithm, Control parameters optimizations. Genetic method
represents a powerful class of computational methodologies
as with GA represents infinite no. of possible algorithm that
can be used to examine combinatorial problem. This means
that the problem should dictate the extract from the algorithm
such as the coding scheme of putative solutions (Niculescu,
2003). This is not probably best suited to examine particular
problems.
Artificial neural network (ANN)
An ANN, often just called a “NN,” is an interconnection
group of artificial neuron that uses a mathematical model or
computational model. Applications of NN can be applied to
business using several different approaches & QSAR
modeling. Turnkey application, NN developed tolls
(commercial packages are Neuro shell brain maker), Used
extensively in the PMH (position specific iterative
predictions), visualizing protein structure & computing
structure properties: Grail gene finder, sequence analysis,
database-searching, pair-wise alignment. The variable
selection in particular important and challenging problem in
the developed of ANN models. Why ANN is useful in that
way? If there deterministic relation between some feature of
the molecules & the property that must be predicted, then
QSAR is amenable to a regression problem i.e. to the
determination of that unknown relation. From a statistical
point of view, NN represents a class of non-parametric
adaptive models (Kustrin, 2001). In this framework, an
important issue is to evaluate the performance of the models.
This is done by separating the data into two sets: The training
set & the testing set. The parameters (i.e. the value of the
synaptic weights) of the network are computed using the
training set.
Self organizing map (SOM)
The SOM is a subtype of ANN. It is trained using unsuper-
vised learning to produce low dimensional representations
of the training sample while preserving the topological prop
38
erties of the input space. The SOM have been used at the
research center in such applications as. Automatic speech
recognition, clinical voice analysis, monitoring of the condi-
tion of industrial plant & process, cloud classification from
satellite images, micro array, analysis of electrical signals
from the brain, organization of & retrieval from large docu-
ment collections, analysis & visualization of large collec-
tions of statistical data. SOMs have also been applied to
studies in the fields of QSAR. The fundamental promise of
QASR studies that structurally related (similar) compounds
will have similar properties determining similarity is a com-
plex tasks, and many method exits such as principal com-
pounds analysis & hierarchical cluster analysis in QSAR
study (Guha, 2004) the use of a SOMs chose the subset of
molecular descriptors to dimensionality of a dataset by vi-
sualizing as a graphical lower dimensional display, & re-
duces the amount of data by representing them with a smaller
no of models ordered on a discrete map lattice.
Support vector machine (SVM)
SVM are a set of related supervised learning methods that
can used for classification and regression. SVM are a set of
related supervised learning method that that can perform
binary classifications (pattern recognitions) & real valued
functions approximations (regression estimations) tasks
SVM non-linearly map their n- dimensional input space into
a high dimensional feature space a linear classifier is
constructed. A special property of SVM is that they
simultaneously minimize the empirical classification error &
minimize geometric margin. SVM was created to address
challenging problems in QSAR analysis. The goal of QSAR
analysis is to predict the bioactivity of molecules. Each
molecule has many potential descriptors that may be highly
correlated with each other or irrelevant to the target
bioactivity (Burbidge, 2001). The bioactivity is known for
only a few molecules. These issues make model validation
challenging and over fitting easy. The results of the SVMs
are somewhat unstable small changes in the training and
validation data or on model parameter may produce rather
different sets of nonzero weight attributes.
Decision Forest
Decision Forest is a decision support tool that uses a graph
or model of decision & their possible consequences. Deci-
sion Forest models often have a degree of accuracy that
cannot be obtained using a large, singletree model. Decision
Forest models are as easy to create as single tree-models, it
can be applied to regression & classification models, the
stochastic (randomization) element in the decision tree for-
est algorithm makes it highly resistant to over, Decision For-
est can handle hundreds or thousands of predictor variables.
It is a novel pattern recognition method, which combines
the results of multiple distinct but comparable decision tree
models to reach a consensus prediction. A decision forest
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39
model was developed using a structurally diverse training
data set. A decision forest model was developed using a
structurally diverse training data set compounds activity
was tested. The model was subsequently validated using a
test data set of compounds selected and then applied to a
large data set with compounds as a screening.
Partial least square
Partial least squares projection to latent structures (PLS) is a
robust using projection to summarize multitudes of poten-
tially collinear variables. Partial least squares projection to
latent structures (PLS) is a robust multivariate generalized
regression method using projections to summarize multitudes
of potentially collinear variables (Waterbeemd, 2008). Multi-
variate statistics is a set of statistical tools to analysis data
(e.g., chemical and biological) matrices using regression and/
or pattern recognition technique. PLS regression technique
is especially useful in quite in common case where the num-
ber of descriptors (independent variables) is compare to or
greater then the no of compounds (data points) and/or there
exist other factors leading to correlations between variables
(Khlebnikov, 2007). Many methodologies have been used in
QSAR modeling such as the PLS here methodologies the
partial least collinear input data to make no restriction on the
number of variables used. PLS leads to stable, correct and
highly predictive models even for correlated descriptors
(Gieleciak 2007).
Multiple linear Regressions
This is a mathematical technique used in both fundamental
& technical analysis. This technique can be used a no. of
variables to predict some unknown variables. In statistics,
regression analysis examines the relation of dependent vari-
ables (response variables) to specified independent vari-
ables (predictors) (Papa, 2007). This assumes that the un-
derlying relationship is linear & that any deviation from lin-
earity will be distributed normally (a parameter assumption).It
also assume that the drug properties are real no & they are
independent each other, so that the affect of one variable is
the other variables. In many QSAR problems it is desirable
to learn relationships that are non-linear.
K-mean clustering
K-means clustering is on an alternative method to the
hierarchical method. It is top-down approach & is useful if
there is prior knowledge about the no. of cluster that should
be represented in the data. In k-means clustering objects are
partitioned into a fixed no (k) of cluster, such that the clusters
are internally similar but externally dissimilar (Mutihac 2008).
The process involve in k-means clustering is as follows. All
initial objects are randomly assigned to one of k clusters
(where k is pre- specified). By using k-means clustering on
experiments with k=2, the data will be partitioned in to two
groups. An average expression vector is calculated for each
cluster & this is used to compute the distances between
GERF Bulletin of Biosciences 2010, 1(1): 37-40
clusters. The expression vectors for each cluster are
recalculated. K-means clustering algorithm use an
interchange (or switching) method to divide n data points
into k group (clusters) is known before clustering. The k-
means clustering results depend on the order of the rows in
the input data, the options k-means initialization, and number
of iteration for minimizing distance. The k means approach
involves ND problems (combinatorial explosion).
Principal component analysis
PCA (also called SVD or singular value decomposition) is
an exploratory technique and it is used to visually estimate
the number of clusters represented n the data. PCA is a
powerful technique for the analysis of QSAR modeling data
when used with other classification technique such as k-
means or SOM [11].
TSAR
Tsar is a fully integrated quantitative structure-activity rela-
tionship (QSAR) package for library design and lead optimi-
zation. Tsar can be used throughout drug discovery, from
initial compound selection for primary screening to reagent
selection and creation of focused libraries for lead optimiza-
tion. Tsar’s easy-to-use chemical spreadsheet interface is
equally accessible to medicinal chemists, computational
chemists and project team leaders (Ivanenkov, 2009).
Advantages of Tsar
Accelerates design and selection of single compounds and
libraries for screening Lets you improve activity and
eliminate undesirable properties in lead optimization.
Typical applications of Tsar:
• Exploring physicochemical properties, 2D or
3D, to understand which promote activity
• Reagent selection by sampling substitute or
reagent properties
• Designing combinatorial libraries by focusing
on desired product properties Similar or diverse
subset selection.
• Developing predictive models of activity.
Conclusion
QSAR model prediction depends on good descriptor selec-
tion because similar molecules with a slight variation in their
structure can have quite different biological activity. This
kind of relationship between molecular structure & change
in biological activity is center of focus for QSAR Modeling.
Correlation analysis and relevant analysis approaches effi-
ciently deals this task. The criteria used for QSAR modeling
was biological-activity relationship within selected descrip-
tors that is efficiently achieved by the descriptor of a set of
64 drugs and their experimentally-derived intestinal absorp-
tion (%) values as descriptor showing 95% correlation. The
application of the QSAR modeling is at developmental phase
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GERF Bulletin of Biosciences 2010, 1(1): 37-40 40

currently. After comparing performance and predictability
in high throughput data mining, researchers from multiple
groups have consistently. Improper descriptors selection
will not lead to reasonable predictions. Correct descriptor
selections rely on understanding the computational problem
that one is trying to solve. Regression analysis and clustering
in the field of QSAR modeling show crucial impact on modern
drug discovery processes. The applications of QSAR
modeling in drug discovery, such as compound selection,
virtual library generation, virtual high throughput screening,
HTS data mining, and in-silico ADMET made it center of
study.
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