Ravichandran Veerasamy, et al : Validation of QSAR Models-Strategies and Importance 511

International Journal of Drug Design and Discovery

Volume 2 Issue 3 July – September 2011. 511-519

Validation of QSAR Models - Strategies and Importance

Ravichandran Veerasamy1*, Harish Rajak2, Abhishek Jain3, Shalini Sivadasan1,

Christapher P. Varghese1 and Ram Kishore Agrawal3
1
Faculty of Pharmacy, AIMST University, Semeling – 08100, Kedah, Malaysia.
2
Institute of Pharmaceutical Sciences, Guru Ghasidas University, Bilaspur-495 009 (CG), India.
3
Department of Pharmaceutical Sciences, Dr. H. S. Gour University, Sagar, India – 470 003.

ABSTRACT: Quantitative Structure-Activity Relationship (QSAR) is based on the hypothesis that changes in molecular
structure reflect changes in the observed response or biological activity. The success of any quantitative structure–activity
relationship model depends on the accuracy of the input data, selection of appropriate descriptors, statistical tools and the
validation of the developed model. Validation is a crucial aspect of QSAR modeling. Validation is the process by which the
reliability and significance of a procedure are established for a specific purpose. Hence in this review we focus on the
importance of validation of QSAR models and different methods of validation.

KEYWORDS: QSAR; Internal validation; External validation; Randomization.

Introduction chemistry, toxicology, and eventually most facets of

A variety of in vitro and computational methods are being
proposed for the toxicological assessment of chemicals
owing to the increasing requirement for alternative
methods to in vivo toxicity testing. More efforts will be
given to include methods such as in vitro techniques and
Quantitative Structure-Activity Relationship (QSAR)
models in the regulatory decision-making process in
Europe1,2 under the new registration, evaluation, and
authorization of chemicals (REACH) system3. For reasons
of practicality, cost effectiveness and animal welfare, it is
envisaged that QSAR will play an important role in the
assessment of existing chemicals for which further
information may be required under the REACH system.
Therefore, it will be essential that the QSAR models used
will produce reliable estimates.
QSAR is a widely accepted predictive and diagnostic
process used for finding associations between chemical
structures and biological activity. QSAR has emerged and
has evolved trying to fulfill the medicinal chemist’s need
and desire to predict biological response4. The quantitative
structure-activity relationship paradigm first found its way
into the practice of agro chemistry, pharmaceutical
* For correspondence:
Tel.: 006-04-4298000 Ext. 1029; Fax: 006-04-4298007.
E-mail: phravi75@rediffmail.com
chemistry. The overall goals of QSAR retain their original
essence and remain focused on the predictive ability of the
approach and its receptiveness to mechanistic
interpretation.
QSAR includes all statistical methods, by which
biological activities (most often expressed by logarithms
of equipotent molar activities) are related with structural
elements (Free Wilson analysis), physicochemical
properties (Hansch analysis), or fields (three-
dimensional QSAR). It is a technique that quantifies the
relationship between structure and biological data and is
useful for optimizing the groups that modulate the
potency of the molecule5.
There are different types of computational methods in
QSAR depends upon the data complexity. Those are two-
dimensional (2D), three-dimensional (3D) and higher
dimensional methods6. 2D-QSAR is insensitive to the
conformational arrangements of atoms in space, while 3D-
QSAR needs information on the position of the atoms in
three spatial dimensions7. In 4D-QSAR for each molecule,
a set of automatically docked orientations and
conformations are developed by genetic algorithms8-12.
Induced-fit scenarios of ligands upon binding to the active
site and solvation models can be thought of as the fifth
(protein flexibility) and sixth (entropy) dimensions in 5D-
and 6D-QSAR, respectively.

511
512 International Journal of Drug Design and Discovery Volume 2  Issue 3 July – September 2011

The process of QSAR model development can be
generally divided into three stages: data preparation, data
analysis and model validation (Scheme 1). These steps
represent a standard practice of any QSAR modeling and
their implementations are often determined by the
researcher’s interests, experience and software availability.
Acquiring a good quality QSAR model depends on many
factors, such as the quality of biological data, the choice of
descriptors, variable selection, statistical methods and
validation13-18.
Validation is a crucial aspect of any QSAR modeling. It
is the process by which the reliability and relevance of a
procedure are established for a specific purpose19. Formal
validation is one of the most overlooked steps in the model
development at many times. In the QSAR community, the
validation of a model is little more than an assessment of
statistical fit and, occasionally, predictivity using cross-
validation techniques. However, it is now being accepted
that validation is a more important process that includes
assessment of issues such as data quality, applicability of
the model and mechanistic interpretability in addition to
statistical assessment20. In this review, we discussed about
the validation parameters for the QSAR models which are
developed by multiple linear regression (MLR) and partial
least square regression (PLS).

Scheme 1 Various stages of QSAR model development

 Ravichandran Veerasamy, et al : Validation of QSAR Models-Strategies and Importance
Importance of validation of QSAR models
The QSAR models are useful for various purposes
including the prediction of activities of untested chemicals.
The success of drug discovery efforts depends heavily on
the use of structure-activity relationship techniques21. Over
the years of development, many methods, algorithms and
techniques have been discovered and applied in QSAR
studies22.
Main challenge in QSAR is to select the group of
descriptors which describe the most critical structural and
physicochemical features associated with activity. Quality
of biological data and effective descriptor or variable
selection is an initial essential part of the QSAR modeling
process23. The application of QSAR models is depends on
statistical significance and predictive ability of these
models. The regulatory decisions, justification of usage
and use of a particular QSAR model is depend on the
model ability to predict unknown chemicals with some
known degree of certainity18,24. QSAR model can lead to
false prediction of biological activity if the developed
QSAR model is not validated. So validation of QSAR
models, after model development, is most important part in
QSAR studies.
QSAR has clearly matured, although it still has a way
to go. The estimation of accuracy of predictions is a critical
problem in QSAR modeling25. Only in this decade,
validation of QSAR models has received considerable
attention14-17, 26-34. Four tools of assessing validity of QSAR
Scheme 2 Various stages of QSAR model validation
513
models35 are (i) cross-validation, (ii) bootstrapping,
(iii) randomization of the response data, and (iv) external
validation. Several principles for assessing the validity of
QSAR models were proposed at an International workshop
held in Setubal (Portugal), which were subsequently
modified in 2004 by the OECD Work Programme on
QSARs1,3. Against this background, in this review we have
discussed about the different validation methods of QSAR
models.
Validation Methods for QSAR Models
Validation methods are needed to establish the
predictiveness of a model on unseen data and to help
determine the complexity of an equation that the amount
of data justifies. Using the data that created the model (an
internal method) or using a separate data set (an external
method) can help validate the QSAR model (Scheme 2).
The methods of least squares fit (R2), crossvalidation
(Q2)36-38 , adjusted R2 (R2adj), chi-squared test (2), root-
mean-squared error (RMSE), bootstrapping and
scrambling (Y-Randomization)39,40 are internal methods of
validating a model. The best method of validating a model
is an external method, such as evaluating the QSAR model
on a test set of compounds. These are statistical
methodologies used to ensure the models created are sound
and unbiased (“good model”). A poor model can do more
harm than good, thus confirming the model as a “good
model” is of utmost importance.
514 International Journal of Drug Design and Discovery Volume 2  Issue 3 July – September 2011
Internal Validation
Least Squares Fit
The most common internal method of validating the model
is least squares fitting. This method of validation is similar
to linear regression and is the R2 (squared correlation
coefficient) for the comparison between the predicted and
experimental activities. An improved method of
determining R2 is the robust straight line fit, where data
points are away from the central data points (essentially
data points a specified standard deviation away from the
model) are given less weight when calculating the R2. An
alternative to this method is the removal of outliers
(compounds from the training set) from the dataset in an
attempt to optimize the QSAR model and is only valid if
strict statistical rules are followed. The difference between
the R2 and R2adj value is less than 0.3 indicates that the
number of descriptors involved in the QSAR model is
acceptable. The number of descriptors is not acceptable if
the difference is more than 0.3.
2
 NXY – (x) (Y)  CV used to measure a model’s predictive ability and
R = 
2
 draw attention to the possibility a model has been over-
 ([NX 2  (X) 2 ] [NY 2  (Y) 2 ]) 
 
Fit of the Model
Fit of the QSAR models can be determined by the methods
of chi-squared (2) and root-mean squared error (RMSE).
These methods are used to decide if the model possesses
the predictive quality reflected in the R2. The use of RMSE
shows the error between the mean of the experimental
values and predicted activities. The chi squared value
exhibits the difference between the experimental and
predicted bioactivities:
n  (y – y ˆ i )2 
2 =   i 
i 1  ŷi  created from the remaining data points using the
 n (yˆ i – y m ) 2 
RMSE = Sqrt  
 i 1 n  1 
Where, y and ŷ are the experimental and predicted
bioactivity for an individual compound in the training set,
ym is the mean of the experimental bioactivities, and n is
the number of molecules in the set of data being examined.
Large chi-square or RMSE values (≥0.5 and 1.0,
respectively) reflect the model’s poor ability to accurately
predict the bioactivities even the model is having large R2
value (≥0.7). For good predictive model the chi and RMSE
values should be low (<0.5 and <0.3, respectively). These
methods of error checking can also be used to aid in
creating models and are especially useful in creating and
validating models for nonlinear data sets, such as those
created with Artificial Neural Network (ANN)41.
However, excellent values of R2, 2 and RMSE are not
sufficient indicators of model validity. Thus, alternative
parameters must be provided to indicate the predictive
ability of models. In principle, two reasonable approaches
of validation can be envisaged one based on prediction and
the other based on the fit of the predictor variables to
rearranged response variables.
Cross-validation
A common method for internally validating a QSAR
model is cross-validation (CV, Q2, q2, or jack-knifing). CV
process repeats the regression many times on subsets of
data. Usually each molecule is left out once (only), in turn,
and the R is computed using the predicted values of the
missing molecule. Sometimes more than one molecule
(leave many out, LMO) is left out at a time. CV is often
used to determine how large a model can be used for a
given data set. A cross-validated R2 is usually smaller than
the overall R2 for a QSAR equation. It is used as a
diagnostic tool to evaluate the predictive power of an
equation.
fitted. Over-fitting refers to the phenomenon in which a
predictive model may well describe the relationship
between predictors and response, but may subsequently
fail to provide valid predictions for new compounds. Over-
fitting of the model is usually suspected when the R2 value
from the original model is significantly larger (25%) than
the Q2 value (Difference between R2 and Q2 should not be
more than 0.3)36. CV values are considered more
characteristic of the predictive ability of the model. Thus,
CV is considered a measure of goodness of prediction and
not fit in the case of R2. The process of CV begins with the
removal of one or a group of compounds, which becomes a
temporary test set, from the training set. A CV model is
descriptors from the original model, and tested on the
removed molecules for its ability to correctly predict the
bioactivities.
In the leave-one-out (LOO) method of CV, the process
of removing a molecule, and creating and validating the
model against the individual molecules is performed for
the entire training set. Once complete, the mean is taken of
all the Q2 values and reported. The data utilized in
obtaining Q2 is an augmented training set of the
compounds (data points) used to determine R2. The method
of removing one molecule from the training set is
considered to be an inconsistent method37,38. A more
correct method is leave-many-out (LMO), where a group
of compounds is selected for validation of the CV model.
This method of cross-validation is especially useful if the
training set used to create the model is small (≤20
 Ravichandran Veerasamy, et al : Validation of QSAR Models-Strategies and Importance
compounds) or if there is no test set. For good
predictability R2 – Q2 value should not exceed 0.3. The
equation for CV is
PRESS
Q2 = 1 – N dependent variables. This procedure ensures that the model
 (yi – y m ) 2
i 1
N
PRESS =  (y pred,i – yi ) 2
i 1
where the yi is the data value(s) not used to construct
the CV model. PRESS is the predictive residual sum of the
squares.
Beware of Q2
To validate a QSAR model, most of researchers apply the
LOO or LMO CV procedures. The outcome from this
procedure is a cross-validated correlation coefficient R2
(Q2). Frequently, Q2 is used as a criterion of both
robustness and predictive ability of the model. Many
authors consider high Q2 (for instance, Q2 > 0.5) as an
indicator or even as the ultimate proof of the high
predictive power of, the QSAR model. They do not test the
models for their ability to predict the activity of
compounds of an external test set (i.e., compounds that
have not been used in the QSAR model development).
There are several examples of recent publications, in which
the authors claim that their models have high predictive
ability without validating them by use of an external test
set42-46. Some authors validate their models by the use of
only one or two compounds that were not used in QSAR
model development47,48 and still claim that their models are
highly predictive. However, it has been found that if a test
set with known values of biological activities is available
for prediction, no correlation may exist between the
predicted and observed activities for the test set49,14.
Bootstrapping
Bootstrapping is another method of internal validation
where samples are selected randomly from the data set. In
the simplest form of bootstrapping, instead of repeatedly
analyzing subsets of the data, sub samples of the data are
repeatedly analyzed. Each sub sample is a random sample
with replacement from the full sample. In a typical
bootstrap validation, K groups of size n are generated by a
repeated random selection of n objects from the original
data set. Some of these objects can be included in the same
random sample several times, whereas other objects may
never be selected. The model obtained from n randomly
selected objects is used to predict the target properties for
the excluded samples. A high average Q2 in the bootstrap
validation is a demonstration of the model robustness.
515
Randomization test (Scrambling model)
The predictive power of the equation is poor when the
observations are not sufficiently independent of each other.
One way to test for this is by randomization of the
is not due to a chance. The set of activity values is
reassigned randomly to different molecules, and repeating
the entire modeling procedure. This process is repeated
many times. If the random models activity prediction is
comparable to the original equation, the set of observations
is not sufficient to support the model.
The creation of a Scrambled Model39,40 is a unique
method of checking the descriptors used in the model
because the bioactivities are randomized ensuring the new
model is created from a bogus data set. The basis for this
method is to test the validity of the original QSAR model
and to ensure that the selected descriptors are appropriate.
These new models (Scram-models) are created using the
same descriptors as the original model, yet the bioactivities
are changed. After each Scram-model is created, validation
is performed using the methods mentioned earlier. To
ensure that the Scram-models are truly random, the process
of changing the bioactivities can be repeated and as each
new Scram-model is created its R2 and Q2 values. Each
time the R2 and Q2 values of the Scram-models are
substantially lower further enforces that the true QSAR
model is sound. The basis of using this method is to
validate the original QSAR model because the Scram-
models are created using the original descriptors and bogus
bioactivities. The model would be in question if there was
a strong correlation (R2 > 0.50)50 between the randomized
bioactivities and the predicted bioactivities, specifically
that the model is not responsive to the bioactivities.
External validation
Several authors have suggested that the only way to
estimate the true predictive power of a QSAR model is to
compare the predicted and observed activities of an
(sufficiently large) external test set of compounds that
were not used in the model development49,50, 51-53. The
problem in external validation is how can we select the
training and test set? Roy et al. clearly discussed that how
we can solve this problem in one of their article22.
To estimate the predictive power of a QSAR model,
Golbraikh and Tropsha recommended use of the following
statistical characteristics of the test set14: (i) correlation
coefficient R between the predicted and observed
activities; (ii) coefficients of determination (R2) [54]
(predicted vs. observed activities r02, and observed vs.
predicted activities r0'); (iii) slopes k and k' of the
regression lines through the origin. They consider a QSAR
516 International Journal of Drug Design and Discovery Volume 2  Issue 3 July – September 2011
model is predictive, if the following conditions are
satisfied14:
R2 pred > 0.6,
r2 – r02 / r2 < 0.1, r2 – r0 ,2 / r2 < 0.1 and
0.85 < k < 1.15 or 0.85 < k’ < 1.15.
The predictive ability of the selected model was also
confirmed by external R2 pred. A value of R2 pred is
greater than 0.6 may be taken as an indicator of good
external predictability.
test
 (yexp – y pred ) 2
R 2Pr ed  1– i 1
test
 (yexp – y tr )2
i 1
Where y tr is the average value for the dependent
variable for the training set.
The lack of the correlation between Q2 and R2 was
noted in, Kubinyi et al.49, Novellino et al.51, Norinder52,
and Golbraikh and Tropsha14, publication, where they
demonstrated that all of the above-mentioned criteria are
necessary to adequately assess the predictive ability of a
QSAR model. Norinder suggest52 that the external test set
must contain at least five compounds, representing the
whole range of both descriptor and activities of compounds
included into the training set.
Recently the use of internal versus external validation
has been a matter of great debate55. One group of QSAR
workers supports internal validation, while the other group
considers that internal validation is not a sufficient test for
checking robustness of the models and external validation
must be done. Hawkins et al., the major group of
supporters of internal validation, are of the opinion that
cross-validation is able to assess the model fit and to check
whether the predictions will carry over to fresh data not
used in the model fitting exercise. They have argued that
when the sample size is small, holding a portion of it back
for testing is wasteful and it is much better to use
“computationally more burdensome” leave-one-out cross-
validation56,57.
Recent term to check the external predictability of the
selected model is r2m, which was proposed by Roy and Paul
(2008) [58] and it was calculated by the following formula
rm2 r 2
1  r 2
 r02  reliable and predictive one?
Where r2 is squared correlation coefficient between
observed and predicted values and r20 is squared
correlation coefficient between observed and predicted
values with intercept value set to zero. A value of r2m is
greater than 0.5 may be taken as an indicator of good
external predictability.
Unlike external validation parameters (R2pred etc.), the
r2m (overall) statistic is not based only on limited number
of test set compounds. It includes prediction for both test
set and training set (using LOO predictions) compounds.
Thus, this statistic is based on prediction of comparably
large number of compounds. The r2m (overall) statistic may
be advantageous when the test set size is considerably
small and regression based external validation parameter
may be less reliable and highly dependent on individual
test set observations. The r2m (overall) statistic may be
used for selection of the best predictive models from
among comparable models are obtained, where some
models show comparatively better internal validation
parameters and some other models show comparatively
superior external validation parameters.
Other validation parameter named as R2p to check the
acceptability of the selected model has been reported by
Roy (2007)55. The parameter R2p, which penalize the model
R2 for the difference between squared mean correlation
coefficient (R2r) of the randomized models and squared
correlation coefficient (R2) of the non-randomized model.
A value of R2p should be greater than 0.5 may be taken as
an indicator of model acceptability.
R 2p  R 2 * 1  R 2  R 2r 
 
The value of r2m (overall) determines whether the range
of predicted activity values for the whole dataset of
molecules are really close to the observed activity or not
(best predictive model or not). The value of R2p, on the
divergent, determines whether the model obtained is really
robust or obtained as a result of chance only. Hence it can
be inferred that a QSAR model can be considered
acceptable if the values of r2m (overall) and R2p are equal to
or above 0.5 (or at least near 0.5).
The selection of robust and well predictive QSAR
models on the basis of R2, Q2 and R2pred may mislead the
search for the ideally predictive model so it may also be
done on the basis of few other parameters, such as R2CVext,
r2 - r20 / r2, r2 - r’20 / r2, k, k’, r2m (overall) and R2p.
When can we accept the developed QSAR model as
A developed QSAR model can be accepted generally in
QSAR (MLR and PLS) studies when it can satisfy the
following criterion (The following values are the minimum
recommended values for significant QSAR model
 Ravichandran Veerasamy, et al : Validation of QSAR Models-Strategies and Importance
meanwhile these evaluation measures are depend on the
response measure scale or measure unit):
 If correlation coefficient R  0.8 (for in vivo data).
 If coefficient of determination R2  0.6
 If the standard deviation s is not much larger than
standard deviation of the biological data.
 If its F value indicate that overall significance level
is better than 95%.
 If its confidence interval of all individual regression
coefficients proves that they are justified at the 95%
significance level.
 If cross-validated R2 (Q2) > 0.5
 If R2 for external test set, R2pred > 0.6
 Randomized R2 value should be as low as to R2.
 Randomized Q2 value should be as low as to Q2.
 (r2 – r20)/r2 < 0.1 and 0.85 < = k < = 1.15, or (r2 –
r'20) / r2 < 0.1 and 0.85 < = k' < = 1.15 (for test set).
 r2m (overall) and R2p are  0.5 (or at least near 0.5).
 In addition, the biological data should cover a range
of at least one, two or even more logarithmic units:
they should be well distributed over whole distance.
Also, physicochemical parameter should be spread
over a certain range and should be more or less
evenly distributed.
Equation has to be rejected
 If the above mentioned statistical measures are not
satisfied
 If the number of the variables in the regression
equation is unreasonably large.
 If standard deviation is smaller than error in the
biological data.
Applicability domain
Activity of the entire universe of chemicals can not be
predicted even by a robust and validated QSAR model.
The prediction of a modeled response using QSAR is valid
only if the compound being predicted is within the
applicability domain of the model. The applicability
domain is a theoretical region of the chemical space,
defined by the model descriptors and modeled response
and, thus, by the nature of the training set molecules59. It is
possible to check whether a new chemical lies within
applicability domain using the leverage approach. A
compound will be considered outside the applicability
domain when the leverage value is higher than the critical
value of 3p/n, where p is the number of model variables
plus 1 and n is the number of objects used to develop the
model.
517
Recently Jaworska et al.60 reviewed the methods and
criteria for estimating applicability domain through
training set interpolation based on range, distance,
geometrical and probability density distribution based
approaches. A cluster-based approach have been proposed
by Stanforth et al.61 to modeling the domain of
applicability by applying an intelligent version of the K-
means clustering algorithm, modeling the training set as a
collection of clusters in the descriptors space, assigning a
test compound fuzzy membership of each individual
cluster from which an overall distance may be calculated.
Guha and Jurs50 have used a classification method that
divides the regression residuals from a previously
generated model into a good class and a bad class and
builds a classifier based on the division. The trained
classifier is then used to determine the class of the residual
of a new compound.
Dispute on QSAR Validation
Hawkins et al., the major group of supporters of internal
validation, are of the opinion that cross-validation is able
to assess the model fit and to check whether the predictions
will carry over to fresh data not used in the model fitting
exercise. They have argued that when the sample size is
small, holding a portion of it back for testing is wasteful
and it is much better to use “computationally more
burdensome” leave-one-out cross-validation56,57.
An inconsistency between internal and external
predictivity was reported in a few QSAR studies 51,52,62. It
was reported that, in general, there is no relationship
between internal and external predictivity63,64: high internal
predictivity may result in low external predictivity and vice
versa. In many cases, comparable models are obtained
where some models show comparatively better internal
validation parameters and some other models show
comparatively superior external validation parameters.
This may create a problem in selecting the final model. So
it is must to develop some good validation techniques to
overcome the entire above mentioned disputes.
Conclusion
Validation of QSAR models is a very important aspect to
understand reliability of model for prediction of a new
compound not present in the data set. If we consider 1000
reported QSAR models, out of which only 50 to 60 models
are really predictive but its not sure that these 60 models
have been obeyed all the conditions and validation
parameters discussed in this articles. Our opinion is, both
internal and external validation strategies are important
and, in fact, one should adopt all available validation
strategies to check robustness of the model. Only few
518 International Journal of Drug Design and Discovery Volume 2  Issue 3 July – September 2011
reported QSAR models were following all the validation
characteristics mentioned in this article65,66.
As a conclusion, not only the above recommendations
for validation of QSAR models by different scientist and
researcher should be followed, also the chemical space of
training and test sets has to be analyzed; real outliers, with
respect to congeneric character and structural similarity,
have to be discovered and eliminated. Even then,
predictions by QSAR models are remains as a risky
procedure. So, still we need proper validation techniques to
select a good predictive QSAR models.
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