J. Chem. & Cheml. Sci. Vol.
3 (2), 48-53 (2013)
Qsar Study of Rabbit Aortic Angiotensin II Antagonists
Compounds Using Different Descriptors
B.N. SINGH1, KALPANA SINGH 1 and KALEEM AHMAD2*
1
Department of Chemistry,
Kisan (P.G.) College Bahraich, U.P., INDIA.
*
Department of Chemistry,
Mahila (P.G.) College Bahraich, U.P., INDIA
(Received on: February 6, 2013)
ABSTRACT
For present study, the various QSAR models have been developed
to predict the activities in terms of log 1/C for 11 Rabbit Aorta
Angiotensin II Antagonists compounds with the help of quantum
chemical and energy descriptors viz. heat of formation, Gibbs free
energy, Molar Refractivity, HOMO energy, LUMO energy,
absolute hardness, Softness, Chemical Potential and
electronegativity. The parameter adopted in this calculation is the
semi-empirical PM3 based. The QSAR model sixth provides a
good arrangement between obs log 1/c & predicted activity.
Keywords: PM3, Absolute Hardness, Global Softness;
electronegativity, Chemical potential, hardness, HOMO, LUMO,
Heat of formation(H), Gibbs free energy (S), Molar
Refractivity (MR).
1. INTRODUCTION
The use of quantitative structureactivity relationships (QSAR) since their
advent in1 has become increasingly helpful
in understanding many aspects of chemicalbiological interactions in drug and pesticide
research as well as many areas of
toxicology. With a properly designed set of
congeners, carefully tested in almost any
biological system, it has become easy to
derive a QSAR by a steadily increasing
number of computerized approaches.
Getting a new QSAR no longer calls for
rushing into print. What is called for is
support for it from as many points of view as
possible. In fact, there are so many fancy
new programs that almost any set of
chemicals acting on a given system can be
correlated mathematically. Some wit has
remarked that if you cannot derive a
correlation equation it is a bad reflection on
your library since there seems to be an
almost unlimited selection of parameters.
Journal of Chemistry and Chemical Sciences, Vol.3, Issue 2, 1 April, 2013 (48-96)
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B. N. Singh, et al., J. Chem. & Cheml. Sci. Vol.3 (2), 48-53 (2013)
The real problem is to deduce when the
result can be related to our general
knowledge of chemistry and biology. For
work in progress, one can test new
molecules to check the equation, but for
most published work, this is not possible.
We are finding that lateral support is
possible in a variety of ways2-10. From the
beginning to present day, luck has played a
major role in drug discovery.11 In the
present report, we review nonpeptide
angiotensin antagonists. The vasoactive
hormone angiotensin II produced by the
renin-angiotensin system (RAS) plays an
integral role in the pathophysiology of
hypertension because it effects the
regulation of fluid volume, electrolyte
balance, and blood volume in mammals.12-13
Renin is a proteolytic enzyme produced
mainly in the juxtaglomerular apparatus of
the kidney, which acts on the circulating globulin angiotensinogen produced by the
liver.14
In the present study we have taken
structures of a set of compounds
Angiotensin II and then compared to the
numerical values of a biological activity.
The goal here has been to find some
numerical information for a molecule. This
structure information and the measured
property or activities are then converted into
a mathematical model of relationship. From
a quality model it is possible to predict and
to design compounds for synthesis and
testing that have a good possibility for
activity. In this paper, the multi linear
regression analysis has been applied for
QSAR study. The relationship has been
worked out between the Log1/C values of a
series of compounds and certain quantum
chemical descriptors.
2. THE STUDY MATERIAL
The compounds taken for study are
Rabbit Aortic derivatives of Angiotensin II
and shown in Fig.-1.
Fig.-1:
3. METHODOLOGY
The Quantum Mechanical QSAR
The Quantum Chemical parameter
based QSAR study was performed by the
following important descriptors like
Chemical
Potential
()16,
Absolute
19
Hardness( ) , Global Softness (S)18,
Electronegativity ()19, Eigen value of
Highest
occupied
molecular
orbital
(EHOMO), Eigen value of lowest
unoccupied molecular orbital (ELUMO),
Heat of formation(H), Gibbs free energy
(S), Molar Refractivity (MR). The
molecules were drawn by spartan06v110,
software and the geometries were optimized
at PM3 level in conjunction with molecular
mechanics. The global hardness and
electronegativities were calculated using
frontier orbital energies obtained from PM3
results and reported in Tables 2. Multiple
linear regression analysis (MLR) is
performed to establish the QSAR.
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B. N. Singh, et al., J. Chem. & Cheml. Sci. Vol.3 (2), 138-147 (2013)
A data set of Rabbit Aortic of
Angiotensin II compounds were taken with
their observed activity is shown in table 1.
Table 1
Comp.No.
1
2
3
4
5
6
7
8
9
10
11
X
H
4-CH3
5-CH3
5-Cl
5-F
5-I
5-C6H5
5-NO2
5-NH2
NHCOCH3
CH3
Y
C3H7
C3H7
C3H7
C3H7
C3H7
C3H7
C3H7
C3H7
C3H7
C3H7
C3H7
Obsd log 1/C
10.100
9.640
8.800
9.070
9.040
8.380
8.910
8.330
7.600
7.900
8.150
Table 2 Calculated numeric values of Rabbit Aortic derivatives of Angiotensin II by using
different descriptors.
E LUMO
(e.v)
-0.914
-1.024
-0.965
-0.944
-1.007
-1.007
-0.828
-0.995
-0.890
-1.001
-0.908
E HOMO
(e.v)
-9.180
-9.351
-9.188
-9.106
-8.989
-8.989
-9.065
-9.145
-9.185
-9.390
-8.732
4.133
4.163
4.111
4.081
3.991
3.991
4.118
4.075
4.148
4.195
3.912
8.087
8.375
8.151
8.047
7.996
7.996
7.857
8.140
8.061
8.391
7.630
5.047
5.188
5.076
5.025
4.998
4.998
4.947
5.070
5.037
5.195
4.820
Multiple linear regression (MLR) analysis
MLR analyses were performed
using Minitab 16 software. The quantum
mechanical descriptors were used as
independent variables and the obsd log1/C50
values as the dependent variables. In the
MR
(cm3/mol)
131.600
130.310
126.110
142.800
155.900
132.600
135.130
143.470
130.640
126.840
132.840
H
(kJ/mol)
227.810
232.710
52.340
304.680
340.500
224.500
261.600
74.320
227.810
252.340
95.590
G
(kJ/mol)
782.850
762.500
579.620
840.970
654.500
945.780
849.300
740.610
782.850
579.620
677.850
statistical analyses, the systematic search
was performed to determine the significant
descriptors. The correlation matrix was
developed to minimize the effect of colinearity and to avoid redundancy and the
variables physically removed from the
analysis, which shows exact linear
Journal of Chemistry and Chemical Sciences, Vol.3, Issue 2, 1 April, 2013 (48-96)
51
B. N. Singh, et al., J. Chem. & Cheml. Sci. Vol.3 (2), 48-53 (2013)
dependencies between subsets of the
variables and multi-co-linearity (high
multiple correlations between subsets of the
variables). The MLR equations of different
QSAR models are as fallowsFirst QSAR model
MLR equation of this QSAR model log 1/C
is given byObsd log 1/C = 2.41 - 6.40 E LUMO
S = 0.520140
PRESS = 3.33043
r^2= 39.2%
Second QSAR model
MLR equation of this QSAR model log 1/C
is given byObsd log 1/C = - 12.3 - 4.76 E LUMO - 1.79
E HOMO
S = 0.431588
PRESS = 2.53884
r^2= 62.8%
Third QSAR model
MLR equation of this QSAR model log 1/C
is given byObsd log 1/C = 43.0 + 25.6 E LUMO + 24.2
E HOMO + 26.1 S
S = 0.439751
PRESS = 2.45686
r^2= 38.65%
PRESS = 4.97156
r^2= 66.9%
Fifth QSAR model
MLR equation of this QSAR model log 1/C
is given byObsd log 1/C = 68.3 + 33.9 E LUMO + 33.1
E HOMO + 34.3 S - 0.0223 MR + 0.00252
H
S = 0.439634
PRESS = 8.14412
r^2= 75.9%
Sixth QSAR model
MLR equation of this QSAR model log 1/C
is given byObsd log 1/C = 48.1 + 19.2 E LUMO + 20.5
E HOMO + 21.1 S - 0.0287 MR + 0.00377
H - 0.00267 G
S = 0.257392
PRESS = 3.44928
r^2= 93.4%
Sixth QSAR model
Fourth QSAR model
MLR equation of this QSAR model log 1/C
is given byObsd log 1/C = 48.1 + 19.2 E LUMO + 20.5
E HOMO + 21.1 S - 0.0287 MR + 0.00377
H - 0.00267 G
S = 0.257392
PRESS = 3.44928
r^2= 93.4%
MLR equation of this QSAR model log 1/C
is given byObsd log 1/C = 39.9 + 22.4 E LUMO + 21.9
E HOMO + 23.7 S - 0.0070 MR
S = 0.470021
This is one of the best QSAR model
in all the six models and has been developed
using E LUMO, ELUMO, Global Softness
(S), Molar Refractivity (MR), Heat of
reaction (H) and Gibbs free energy
Journal of Chemistry and Chemical Sciences, Vol.3, Issue 2, 1 April, 2013 (48-96)
52
B. N. Singh, et al., J. Chem. & Cheml. Sci. Vol.3 (2), 138-147 (2013)
N ormal P robability P lot
(response is Obsd log 1/C )
99
95
90
80
Percent
70
60
50
40
30
20
10
5
-2
-1
0
Re s idua l
Fig: - 1 Normal probability plot of responses of QSAR model Sixth
4. CONCLUSION
REFERENCES
Values of the descriptors of the
Angiotensin II Antagonist derivatives have
been calculated using PM3 method and are
given in Table-2. With the help of these
values of descriptors, six QSAR models
have been developed using MLR analysis in
different combinations of descriptors. The
Chemical Potential () and Absolute
Hardness ( ) descriptors have no predicting
power and hence not included in the models.
Best QSAR models is the model sixth listed
below-
1. Hansch, C.; Maloney, P. P.; Fujita, T.;
Muir, R. M. Nature,194, 178 (1962).
2. Hansch, C. Acc. Chem. Res., 26, 147
(1993).
3. Hansch, C.; Hoekman, D.; Gao, H.
Chem. Rev., 96, 1045 (1996).
4. Gao, H.; Hansch, C. Drug Metab. Rev.
18, 513 (1996).
5. Hansch, C.; Gao, H. Chem. Rev., 97,
2995 (1997).
6. Hansch, C.; Gao, H.; Hoekman, D.
Comparative QSAR; Devillers,J., Ed.;
Taylor and Francis: London,p 285
(1998).
7. Gao, H.; Katzenellenbogen, J. A.; Garg,
R.; Hansch, C. Chem.Rev.,99,723 (1999.
8. Selassie, C. D.; Shusterman, A. J.;
Kapur, S.; Verma, R. P.; Zhang, L.;
ACKNOWLEDGEMENT
We are thankful to Dr. A.M. Sexana
of C.D.I.R & I.T.RC., Lucknow for
providing laboratory facility.
Journal of Chemistry and Chemical Sciences, Vol.3, Issue 2, 1 April, 2013 (48-96)
53
9.
10.
11.
12.
13.
B. N. Singh, et al., J. Chem. & Cheml. Sci. Vol.3 (2), 48-53 (2013)
Hansch, C. J. Chem. Soc., Perkin Trans.
2, 2729 (1999).
Garg, R.; Gupta, S. P.; Gao, H.; Babu,
M. S.; Debnath, A. K.; Hansch, C.
Chem. Rev., 99, 3525 (1999).
Hansch, C.; Kurup, A.; Garg, R.; Gao,
H. Chem. Rev., 101, 619 (2001).
Hansch, C. J. Chem. Educ., 51, 360
(1974).
Peach, M.J. Physiol. Rev.,57, 313 (1977).
Dzau, V. J.; Pratt, R. E. Handbook of
Experimental Cardiology; Haber, E.,
Morgan, H., Katz, A., Fozard, H., Eds.;
Raven: New York,p D1631 (1986).
14. Ondetti, M. A.; Cushman, D. W. J. Med.
Chem., 24, 355 (1981).
15. Mulliken R S, J. Chem. Phys. 2, 782
(1934).
16. Parr R G and Pearson R G. J. Am. Chem.
Soc. 105, 7512 (1983).
17. Pearson, R. G. J. Am. Chem. Soc. 85,
3533-3539 (1963).
18. R.G. Parr, R.G. Pearson, Journal of the
American Chemical Society 105 (26),
7512 e7516 (1983)
19. R. Iczkowski, J.L. Margrave, Journal of
the American Chemical Society 83 (17),
3547 (1961).
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