Volume 4, Issue 6, November-December 2015

ISSN No.: 2319-7536

Available Online at www.gpublication.com/crbps
Genxcellence Publication 2015-19, All Rights Reserved

RESEARCH PAPER
Quantitative Structure Activity Relationship (QSAR) Studies of Some Novel Anti-
diabetic Drugs
Gaurav Bajpai*, Suman Malik
Sadhu vaswani college, Bairagarh, Bhopal
Mail Id; gauravbajpai22@gmail.com

Abstract

Diabetes is a metabolic disorder characterized by resistance to the action of insulin, insufficient insulin secretion, or both. The clinical
manifestation of these disorders is hyperglycemia.The primary goals of DM management are to reduce the risk for microvascular and
macrovascular disease complications, to ameliorate symptoms, to reduce mortality, and to improve quality of life.PPARs are members of
the nuclear receptor family that play a central role in the regulation of storage and catabolism of dietary fats. The three subtypes of
PPAR (designated a, g and b/d) bind to fatty acids (FFAs) and FFA metabolites and regulate the expression of genes involved in the
transport, metabolism and buffering of these ligands within cells.Thiazolidinedionesbased antidiabetic drugs such as pioglitazone,
rosiglitazone and triglitazone have associated side effects such as weight gain, edema and anaemia. Thus QSAR approach is used in this
research paper to develop a potent thiazolidinediones based antidiabetic compound free from side effects.

Keywords

QSAR, SAR, Thiazolidinediones, Diabetes, PPARs etc.

1. INTRODUCTION potential of PPARg agonists along with beneficial lipid

Diabetes is a group of metabolic disorders characterized by
hyperglycemia. It is associated with abnormalities in
carbohydrate, fat, and protein metabolism and results in
chronic complications, including microvascular,
macrovascular, and neuropathic disorders. The dietary
carbohydrates are metabolized to glucose in our body, which
are further utilized for the production of energy with the
help of a hormone insulin. In diabetic patients the utilization
of glucose for the production of energy in the human body is
affected, thus resulting in the increased level of glucose in
blood [12].
Diabetes is a metabolic disorder characterized by resistance
to theaction of insulin, insufficient insulin secretion, or
both.The clinicalmanifestation of these disorders is
hyperglycemia. The vast majorityof diabetic patients are
classified into one of two broad categories:type 1 diabetes
caused by an absolute deficiency of insulin, or type
2diabetes defined by the presence of insulin resistance with
an inadequatecompensatory increase in insulin secretion [1].
The primary goals of DM management are to reduce the risk
for microvascular and macrovascular disease complications,
to ameliorate symptoms, to reduce mortality, and to improve
quality of life. Near-normal glycemia will reduce the risk for
development of microvascular disease complications, but
aggressive management of traditional cardiovascular risk
factors (i.e., smoking cessation, treatment of dyslipidemia,
intensive blood pressure control, and antiplatelet therapy)
are needed to reduce the likelihood of development of
macrovascular disease [2].
PPARs are members of the nuclear receptor family that play
a central role in the regulation of storage and catabolism of
dietary fats. The three subtypes of PPAR (designated a, g
and b/d) bind to fatty acids (FFAs) and FFA metabolites and
regulate the expression of genes involved in the transport,
metabolism and buffering of these ligands within cells. In
particular, PPARa/g dual agonists exhibit insulin sensitizing
modulating activities of PPARaagonists. Dual-acting
PPARa/g agonists, therefore, could simultaneously correct
insulin resistance and lipid imbalance, thereby overcoming
the side effects of selective PPARg agonists. For this reason,
they are considered a very attractive option in the treatment
of dyslipidemic type 2 diabetes [12].
2. MATERIAL & METHODS
Multiple regression analysis was performed to carry out
QSAR study with Hansch approach on glycine site of
NMDA receptor for three different series.
Physicochemical parameters for substituents of unionized
molecules like calculated log of partition coefficient in
octanol/water (ClogP). Verloops STERIMOL (L1 and B1-
5) were obtained from MMP plus. ClogP is a
lipophilicity measure. Calculated Molar refractivity
(CMR) is based on Lorentz-Lorenz equation: CMR=(n2-
1)/(n2+2)(MW/d) where n is the index of refraction, MW
is molecular weight of the compound and d is density.
The interesting aspect of CMR is its dependency on
combined effect of molecular volume and polarizability
represented by MW and n respectively. However, the
effect of polarizability is less, as for most compounds nis
in the range of 1.35-1.60. Physicochemical parameters for
substituents of ionized molecules at pH=7.4 like
calculated log of partition coefficient in octanol/water
(ClogD) and CMR were obtained from Marvin
The polarisability portion (n2-1)/(n2+2) is not a
satisfactiory way to assess polarisability since it cannot
account for the directional, three-dimensional nature of
the effect of electron movement. The refractive index is
simply a rough measure. Still, it is clearly important in a
number of QSARs.
It is assumed that CMR is a much better parameter than
molecular volume (MV). B1 is a measure of the width of
the first atom of a substituent and B5 tends to measure
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 Gaurav Bajpai et al, Current Research in Biological and Pharmaceutical Sciences, 4 (6) November-December 2015,17-24

width of the whole substituent. B5 is a better measure

when first atom is common in all substituents in a series. 3. RESULTS AND DISCUSSION:
L1 is the length of the substituent. The indicator variable
I is assigned a value of 1 or 0 for special features with Following QSAR equations for various series ofPPAR
special effects that cannot be parameterized, and has been agonists were obtained.
explained wherever used. 1. One series of bioisostericoximes of ligand LT175
Self-generated software was obtained from Chemistry (2(S)-(Biphenyl-4-yloxy)-3-phenyl-propionic acid)
Group, BITS-Pilani to evolve the QSAR equations, which (http://dx.doi.org/10.1016/j.ejmech.2014.11.044)
provides correlation coefficient (r), standard deviation (s), R2
and ratio between variance of calculated and observed O O
activites (F).F represents the Fischer statistics (Fischer O N C
ratio), F= fr2/[(1-r2)m], where f is the number of degrees R1 OH
of freedom [f=n-(m+1)], n is the number of data points
and m is the number of variables. The larger value of F
indicates higher probability of QSAR equation being
significant.The software also provides intercorrelation I
matrix between descriptors and is given hereforth with Loiodice. et al. studied structure activity relationships of I as
every training set equation in the form of a table. For PPAR receptor agonists (Table 1).
internal validationR2(=r2), R2A and Q2 were calculated. R2 Table 1: Structure Activity Relationship study of (I) as
is variance between observed and calculated logEC50. PPAR receptor agonists.
R2A is the adjusted R2, calculated by the formula, R2A=R2 C.N. R1 R2 EC50(M)*
(1-1/F). It is believed that closer the value of R2 to unity 1 H H 43.0
better is the QSAR model. (S)-1 H H 28
Q2 is variance between observed and cross-validated 2 CH3 H 12.8
leave-one-out (L-O-O) logIC50 or logKi. A squared 3 (CH2)2CH3 H 7.9
correlation was also calculated between CMR and ClogP. (S)-3 (CH2)2CH3 H 3.8
Quality (Qy) of the model was calculated by the ratio r/s. 4 (CH2)3CH3 H 3.65
Chance correlation due to excessive number of 5 (CH2)6CH3 H n.c.
parameters (which also increases r and s values) can, 6 CH(CH3)2 H 5.6
therefore, be detected by the examination of the Qy value. 7 CH2CH(CH3)2 H 4.5
High values of Qy indicate high predictive power of 8 CH2Ph H 2.1
QSAR models and lack of over-fitting. 9 (CH2)2Ph H 1.8
Bilin software was used to generate the Kubinyis bilinear
10 (CH2)3Ph H 1.25
equations. The activities of the compounds were
11 H H 9.4
converted into moles and a negative logarithm was taken
12 H Ph 12.4
in order to bring out better correlations and avoid
clustering of data points. The data table depicts biological E-13 (CH2)2CH3 Ph 1.0
activity -logEC50 viz. observed (Obs.), calculated from Z-13 (CH2)2CH3 Ph 0.68
equation obtained through software (Cal.) and external n.c.: not computable. * Efficacy values were calculated as the
prediction (Ext. Pred.). Difference indicates difference in % of the maximum obtained fold induction with the
Obs. and Cal. activities.Removing test set compounds reference compound rosiglitazone.
randomly from the training set and developing equations EQUATION (1): Significant
without them provided predicted activities of the test set. -logEC50 = 0.436(0.082)ClogD +4.776(0.141)
The test set constituted 25% of the training set and is n = 14 r = 0.958 s = 0.150 F(1,12) = 134.25 r2=0.92
mentioned as predicted activity. Acceptance criteria: r2A=0.91 Qy=6.39 Q2=0.85 sPRESS=0.21
R2>0.6 and Q2>0.5.Outliers were not included in the outlier: C.N. 12
derivation of a QSAR equation and are indicated after the EQUATION (2): Significant
QSAR equation. Compounds were deemed to be outliers (After removing test set C.N. 1,3,5 and 7 and outlier C.N.
on the basis of their deviation between Obs. and Cal. 13)
activities if Obs.-Cal.>2s. Biological activity of outliers -logEC50 = 0.408(0.105)ClogD +4.824(0.208)
was also calculated from the final model. A good n = 10 r = 0.953 s = 0.151 F(1,8) = 79.906r2=0.91 r2A=0.90
spreadability of the descriptor values of the substituents Qy=6.31 Q2=0.85 sPRESS=0.21
reduces bias in the QSAR equation and makes the activity EQUATION (3):Significant
prediction power of the model much more accurate. It is -logEC50 = 0.035(0.007)CMR +1.569(0.716)
depicted in the form of a table with every QSAR n = 14 r = 0.958 s = 0.150 F(1,12) = 134.648
equation. Equation (1) represents highly significant correlation
Following series were subjected to QSAR analysis as accounting for 92% of variance (Figure 1) in activity with
PPARreceptor agonists. one outlier excluded. ThePPAR agonist binding activity of
1. One series of bioisostericoximes of ligand LT175 Table 1 compounds was found to have a linear correlation
(2(S)-(Biphenyl-4-yloxy)-3-phenyl-propionic acid) with ClogD of whole molecule at pH=7.4. A coefficient of
(http://dx.doi.org/10.1016/j.ejmech.2014.11.044) 0.436 indicates partial desolvation of ligands at the time of
2. Two series of oxyiminoalkanoic acids(Chem. binding with the receptor. This indicates that the binding site
Pharm. Bull. 51(2) 138151 (2003)) is close to surface of the receptor. The EC50 value of the
outlier was calculated using equation 1. It is marked in
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Table 2. A test set of 25% molecules was removed randomly
and another equation (2) was obtained with a high
correlation explaining 91% of variance in activity with one
outlier excluded. The EC50 value of test set molecules was
calculated with equation (2) and is marked in Table 2. The
difference between these externally predicted EC50 values
and experimental EC50 values is very less which indicates
the robustness and high predicting nature of equation (1).
Equation (3) was also found to be significant with a high
correlation in a linear relationship with CMR. But a high
intercorrelation between ClogD and CMR was found
(r2=0.95) which indicates that either of the two equations
(Eq 1,3) could be utilized for prediction of PPAR activity.

Table 2: A series of bioisostericoximes of ligand LT175with their lipophilic and in-vitro PPAR- agonist EC50 values.
Observed Calculated Externally Predicted
C.N. ClogD Difference
-log EC50 -log EC50 -log EC50
1 -0.32 4.4 4.6 -0.2 4.7
S-1 -0.32 4.6 4.6 0.0
2 0.26 4.9 4.9 0.0 4.9
3 1.14 5.1 5.3 -0.2
S-3 1.14 5.4 5.3 0.1 5.3
4 1.59 5.4 5.5 -0.1
6 1.04 5.3 5.2 0.1 5.2
7 1.51 5.3 5.4 -0.1
8 1.99 5.7 5.6 0.1
9 2.28 5.7 5.8 -0.1
10 2.72 5.9 6 -0.1
11 -0.26 5 4.7 0.3
12 1.58 4.9 5.4 0.5
E-13 2.84 6 6 0.0
Z-13 2.84 6.2 6 0.2

6
5
4 R = 0.917
-logEC50 3
2
1
0
-1 0 1 2 3
ClogD

Fig1: Linear relationship between ClogD and logEC50.

First series of oxyiminoalkanoicacids(Chem. Pharm. Bull. 51(2) 138151 (2003))

N O O R1

N
O
R2
II
Table 3:Structure Activity Relationship study of (II) as PPAR receptor agonists.
C.N. R1 R2 Position EC50(M)*
26 phenyl CH2CO2H 4 0.053
27 phenyl (CH2)2CO2H 4 0.024
28 phenyl (CH2)2CO2H 3 0.020
29 phenyl (CH2)2CO2H 2 0.69
30 phenyl (CH2)3CO2H 4 0.062
31 phenyl (CH2)4CO2H 4 0.0025
32 (CH2)4COOH phenyl 4 0.056

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33 phenyl (CH2)4CO2H 3 0.0035

34 phenyl (CH2)5CO2H 4 0.0039
35 phenyl (CH2)6CO2H 4 0.26
36 phenyl (CH2)7CO2H 4 12
37 4-fluorophenyl (CH2)2CO2H 4 0.047
38 4-phenoxyphenyl (CH2)2CO2H 4 0.048
39 2-pyridyl (CH2)2CO2H 4 0.045
40 3-pyridyl (CH2)2CO2H 4 0.25
41 4-pyridyl (CH2)2CO2H 4 0.17
42 phenyl CONH(CH2)2CO2H 4 0.11
43 phenyl CH2CONHCH2CO2H 4 0.38
44 phenyl (CH2)3C(CH3)2CO2H 4 0.032

45 N O O R1 0.83
N
O
R2

* EC50, the concentration of test compound required to induce 50%of the maximum activity.
EQUATION (4):Significant
-logEC50 = 1.794(0.635)ClogD -0.396(0.122)ClogD2 +5.466(0.711)
n = 14 r = 0.921 s = 0.274 F(1,12) = 30.757r2=0.85 r2A=0.82 Qy=3.36 Q2=0.66 sPRESS=0.448
optimumClogD (ClogDo)=2.27 (2.02-2.46)
Outlier: C.N. 29,31,33,34,44,45
EQUATION (5): Significant
(After removing test set C.N. 38,39,41,43 and outliers C.N. 29,31,33,34,44,45)
-logEC50 = 1.834(0.597)ClogD -0.405(0.106)ClogD2 +5.408(0.760)
n = 10 r = 0.974 s = 0.183 F(1,8) = 64.320r2=0.95 r2A=0.94 Qy=5.32
-logEC50 values for the test set molecules (C.N. 38,39,41,43) were predicted using equation number (5) and are available in Table
4.
EQUATION (6): Significant.
Bilinear model with ClogD
-logEC50 = 0.494(0.24)ClogD - 2.989(0.84)log(*10ClogD + 1)+ 6.367 (0.46)
n = 14 r = 0.939 s = 0.275 F(1,12) = 25.014
log = -3.473 ClogDo= 2.77
EQUATION (7):Insignificant
-logEC50 = -0.216(0.336)ClogD +7.431(0.847)
n = 14 r = 0.375 s = 0.652 F(1,12) = 1.959
Outlier: C.N. 29,31,33,34,44,45

Equation (4) represents highly significant correlation
accounting for 85% of variance (Figure 2) in activity.
ThePPAR agonist binding activity of Table 3 compounds
was found to have a non linear closed parabolic correlation
with ClogD of whole molecule at pH=7.4.The equation
depicts an optimum ClogD of 2.27 for maximal biological
activity. The EC50value of the outliers was calculated using
equation 4. They are marked in Table 4. A test set of 25%
molecules was removed randomly and another equation (5)
was obtained with a high correlation explaining 95% of
variance in activity. The EC50 value of test set molecules
was calculated with equation (5) and is marked in Table 4.
The difference between these externally predicted EC50
values and experimental EC50 values is very less which
indicates the robustness and high predictive nature of
equation (4).

Table 4: First series of oxyiminoalkanoicacidswith their lipophilic valuesandin-vitroPPAR agonist EC50 values.(Chem.
Pharm. Bull. 51(2) 138151 (2003))
Externally
Observed Calculated
C.N. ClogD Difference Predicted
-logEC50 -logEC50
-log EC50
26 2.11 7.3 7.5 -0.2
27 2.12 7.6 7.5 0.1
28 2.10 7.7 7.5 0.2
29 1.99 6.2 7.5 1.3
30 2.61 7.2 7.4 -0.2
31 3.12 8.6 7.2 1.4
32 3.12 7.3 7.2 0.1
33 3.10 8.5 7.2 0.7
34 3.47 8.4 6.9 1.5

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35 3.94 6.6 6.4 0.2

36 4.71 4.9 5.1 -0.2
37 2.16 7.3 7.5 -0.2
38 3.41 7.3 7.0 0.3 7.0
39 1.11 7.3 7.0 0.3 6.9
40 0.71 6.6 6.5 0.1
41 0.70 6.8 6.5 0.3 6.5
42 1.27 7.0 7.1 -0.1
43 1.16 6.4 7.0 -0.6 7.0
44 4.25 7.5 6.9 0.6
45 1.67 6.1 7.4 1.3
8 R = 0.847
7.5
7
6.5
-logEC50 6
5.5
5
4.5
4
0 1 2 3 4 5
ClogD

Fig2: Nonlinear parabolic relationship between ClogD and logEC50.

Second series of oxyiminoalkanoicacids(Chem. Pharm. Bull. 51(2) 138151 (2003))

N
O

Het (CH2)nCOOH
(CH2)m
III
Table 5:Structure Activity Relationship study of (III) as PPAR receptor agonists.
C.N. Het m n EC50(M)*

N
46 1 2 0.25
O

N
47 1 2 0.16
S

48 1 2 0.98
N O

49 1 2 0.31
O N

N
50 1 2 0.36
S
O N
51 1 2 0.042
O

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 Gaurav Bajpai et al, Current Research in Biological and Pharmaceutical Sciences, 4 (6) November-December 2015,17-24

S N
52 1 2 0.017
O

53 2 2 0.91
N N

N
54 2 2 2.1
N N

N
55 2 2 0.34
O
O N
56 1 4 0.0049
O
S N
57 1 4 0.00084
O

* EC50, the concentration of test compound required to induce 50% of the maximum activity.
EQUATION (8):Significant
-logEC50 = 0.112(0.046)CMR -9.156(6.655)
n = 10 r = 0.893 s = 0.498 F(1,8) = 31.521r2 = 0.80 r2A= 0.77 Qy=1.79 Q2=0.70 sPRESS=0.64
outliers: C.N. 49 and 54.
The calculated logEC50 values for the outliers were obtained from equation number (8).
EQUATION (9):Significant
(After removing test set C.N. 45,47,51 and outliers C.N. 49,54)
-logEC50 = 0.109(0.056)CMR -8.753(8.210)
n = 7 r = 0.912 s = 0.506 F(1,5)= 24.789r2 = 0.83 r2A= 0.80 Qy=1.80
EQUATION (10):Insignificant
-logEC50 = 0.469(1.001)ClogD +5.950(2.183)
n = 12 r = 0.313 s = 0.974 F(1,10) = 1.090

Equation (8) represents highly significant correlation
accounting for 80% of variance (Figure 3) in activity with
two outliers excluded. ThePPAR agonist binding activity of
Table 5 compounds was found to have a linear correlation
with CMR of whole molecule. The EC50 value of the
outliers was calculated using equation 8. It is marked in
Table 6. A test set of 25% molecules was removed randomly
and another equation (9) was obtained with a high
correlation explaining 83% of variance in activity. The EC50
value of test set molecules was calculated with equation (9)
and is marked in Table 6. The difference between these
externally predicted EC50 values and experimental EC50
values is very less which indicates the robustness and high
predicting nature of equation (8). Equation (10) was found
to be non-significant with ClogD. A low intercorrelation
between ClogD and CMR was found (r2=0.51) which
indicates that polarizability of the molecules has a role to
play for prediction of PPAR activity.

Table 6: Second series of oxyiminoalkanoicacidswith their lipophilic valuesandin-vitro PPAR- agonist EC50 values.(Chem.
Pharm. Bull. 51(2) 138151 (2003))
Externally
Observed Calculated
C.N. CMR Difference Predicted
-logEC50 -logEC50
-log EC50
45 147.47 6.6 7.0 -0.4 7.3
46 151.97 6.8 7.4 -0.6
47 138.27 6.0 6.3 -0.3 6.3
48 138.12 6.5 6.3 0.2
49 157.03 6.4 8.4 2.0
50 145.01 7.4 6.8 0.6
51 149.51 7.8 7.2 0.6 7.5
52 134.25 6.0 6.0 0.0
53 132.70 5.7 5.8 -0.1

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54 157.32 6.5 8.5 2.0

55 154.22 8.3 8.5 -0.2
56 158.71 9.1 8.9 0.2

9.5 R = 0.797
9
8.5
8
7.5
-logEC50
7
6.5
6
5.5
5
130 135 140 145 150 155 160 165
CMR

Fig3: Linear relationship between CMR and logEC50.

Proposed Molecules:From equation (4) it is deduced that a
ClogD of 2-2.5 could be kept to get maximal EC50 value. In
this regard from series compounds of (I) we have done a
slight modification in compounds E-13 and Z-13 by
introducing an alcoholic group in phenyl ring attached to
oxime group. This reduced its ClogD from 2.8 to 2.5 while
keeping all substituents intact which would be required to
make polar and non-polar interactions with the binding site.
These are proposed molecules E-P1 and Z-P1.
OH
O O OH
N
O
E-P1 and Z-P1
Similarly we have added a para alcoholic OH group in the
phenyl moiety in compound number 31attached to oxyimino
group of series II which rendered ClogD reduced to 2.68
from 3.12 much closer to optimum ClogD range of 2-2.5.
This is third proposed molecule P2.
OH
N functional groups. This reduced their ClogD and made them
O O
N
O OH
on one series of bioisostericoximes of ligand LT175 (2(S)-
(Biphenyl-4-yloxy)-3-phenyl-propionic acid) and two series
of oxyiminoalkanoic acid analogues as PPAR agonists.
Different parameters like ClogD,CMR and molecular weight
were utilized which were calculated from authentic and
validated softwares. Significant equations were obtained
with ClogD and CMR which indicated the importance of
bulkiness and polarizability of PPAR ligands. The
equations obtained were statistically validated and their
predictive power was ascertained by removing a test set and
then recalculating their biological activity with the new
equation obtained with the training set. Eq 1 indicated the
importance of linear relationship of ClogD with EC50 in
bioisostericoximes of ligand LT175 (I). Equation 4 indicated
a closed parabolic non-linear relationship of ClogD with
EC50 in first series of oxyiminoalkanoic acid analogues (II).
It also indicated that an optimal value of ClogD 2.27 (2.02-
2.46) is required for maximum EC50 in this class of series. A
bilinear bobel of kubinyis type was also obtained in
equation 6 which was found to be significant. Equation 8
indicated importance of CMR in second series of
oxyiminoalkanoic acid analogues (III). Utilizing the clue of
optimum ClogD from equation 4 newer ligands (E-P1,Z-P1
and P3) were proposed by making slight modifications in
the chemical structure through the introduction of para
alcoholic groups in the phenyl rings attached to the
more compliant towards optimum ClogD range. It would be
interesting to synthesize these proposed molecules and
determine their EC50 values as PPAR agonists.

O
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