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ABSTRACT
The present paper deals with the investigation of HIV HIV- Table 1.It is divided into training (34 compounds) and
RT inhibitory activity of 45 compounds. Different test set (11). The
he topological indices used for modeling
topological parameters, including distance based HIV-RTRT inhibitors were calculated using DRAGON
topological and connectivity indices have been chosen [13] software and are presented in Table 2. This table
for modeling pIC50 activity of these compounds. T The also includes observed activity value of the compounds
MLR shows that the best model is obtained using a five used in the present study (pIC50).The correlation among
parametric model containing Jhete, Jhetp, 4χ, logP, χeq. thee topological indices is calculated by using
The QSAR model derived from the above mentioned correlation matrix which is reported in Table 3.While
descriptors were found to be statistically significant and performing variable selection for multiple regression
exhibited superior predictive power. r. The correlation using all the DRAGON descriptors together with
between calculated and experimental activity was 0.79 equalized electronegativity we observed that out of all
and the reliability of the model was validated with the descriptors used equalized electronegativity (χeq) is
leave-one-out cross-validation
validation method. Its predictive the descriptor to start one-variable
variable modeling of HIV-
HIV
capability was further validated using a test set of 11 RT inhibition. Also, that all the models obtained during
inhibitors similar to the training set of inhibitors. variable selection invariably contain χeq as one of the
correlating descriptor indicating
indicatin that χeq plays a
Keywords: HIV-RT,
RT, connectivity indices, log P, QSAR, dominating role in modeling HIV-RT
HIV inhibition. The
MLR results obtained herein indicated that more reliable
models can be obtained when χeq is combined with
Introduction
other topological indices.
When Human Immunodeficiency virus attacks the
At this stage it is worthy to mention that when two or
living system, the result is very serious as it breaks
more
ore atoms initially of different electronegativities
down the body’s immune system and results into a
combine chemically, they adjust to same intermediate
deadly disease known as AIDS [1,2] This virus is a
electronegativity with in the compound. That is, the
type of retrovirus which has a reverse transcriptase
electron will flow from the more electronegative atom
(RT). Scientists who have worked for many years took
creating a partial positive charge on the former
f and
interest in this field and ultimate solution to this
partial negative charge on the later. As the positive
problem is obtained in the form of HIV-RT,
RT, an enzyme
charge on the electropositive atom increases, its
which converts viral RNA into a double stranded viral
effective nuclear charge increases. Hence, its
DNA which allows HIV to integrate into human
electronegativity increases. The same trends happening
Computational Details in the opposite direction for the more electronegative
e
atom until two have the same electronegativity. This
The structural details of the 45 compounds are given in principle has gained wide acceptance [12-16].
[12 In the
frame of the Sanderson’s principle [17], it is generally and 3 for single, an aromatic, double and triple bond
believed that partial charge acquired by an atom respectively.
through chemical combination is proportional to the
difference between the final equalized electronegativity Randic Molecular Connectivity Index
and the initial pre-bonded
bonded electronegativity charge
The branching or connectivity index originally defined
conservation equation leads to a general expression for
by Randic [22] is referred to as the path-1
path molecular
equalized electronegativity (χeq) 1 1
connectivity χ. The value of χ reflects both the size
χeq= N/Σ V/X ` [1] and the branching of the structure. It is related to the
size of the molecule because when extra atoms and
Where N is the total number of atoms in the species bonds are added, more terms are added to the
formula, V is the number of atoms of a particular summation, and the value grows.1χis also related to the
element in the species formula and χis the degree of branching of the molecule because, when
electronegativity of particular atom. Earlier Agrawal more branching occurs, the denominators for those
and Khadikar[18] have successfully
ssfully used equalized terms become larger and the terms themselves
them become
electronegativity for modeling toxicity of nitrobenzene smaller, thus decreasing the overall value for the
derivatives in which they have obtained reasonably index.Randic molecular connectivity index is defined
good results by combining χeq with other topological as
indices. There also they observed that out of several
descriptors used it was χeqalone which gave statistically
significant one-variable
variable model. In the present study
D D
edges ij
i j
1 2
[5]
therefore, we have used χeq along with few other
topological indices for modeling HIV-RT RT inhibitors. Di and Dj - the edge degrees (atom connectivity) of the
molecular graph.
Balaban Heteroatom Index (Jhet)
Randicindices of different orders
This is an extension of Balabann index (J) [19
[19-21] to
The bond parameter kr is given by the following The compounds used in the present study have been
expression: listed in Table 1. Those with * denotes the compounds
used for test set and remaining are in the training set.
kr = 1/ wr X (Zc) 2/ (Zi + Zj) [4] The topological parameters along with biological
activity in the form of pIC50have
pIC50hav been summarized in
Table 2. Table 3 demonstrates the correlation matrix
Where wr is the bond weight with values of 1, 1.5,2,
showing inter correlation among all the parameters. A 2. Further improvement is observed when Jhete, Jhetp,
close observation of this table clearly indicates that: logP, 4ᵡ and ᵡeq have been taken together resulting
into a five-parametric model (model 18, Table 4).
1. No mono-parametric correlation is capable Here R2 is 0.7926 and Pogliani’s quality factor has
ofmodeling the pIC50 value of present set of a value 17.2870. This value is the highest among all
compounds;however logP, Jhetp and ᵡeq are the most the models.
suitable parameters to be used in multiparametric
modeling. Therefore the five parametric model is the best model
4
for modeling the pIC50 activity of compounds used in
2. ᵡ and Jhete are moderately correlated whereas J hete the present study.
and Jhetp also show good correlation.However, this
correlation has a lower magnitude than the previous From the calculations, it is observed that statistically
one. significant models start pouring from three-variable
model (model-14, Table 4). Also, that the proposed
The entire data setis divided into training and test sets. models invariably contain equalized electronegativity
The training set was subjected to regression analysis (χeq) as one of the correlating parameters. This
using NCSS software. All thestatistically significant demonstrates the dominating role of χ eq in modeling
models along with their quality have been summarized HIV-RT inhibitors. Further it is also observed that the
in Table 4. This Table also includes the values of proposed models contain logP as correlating parameter.
Pogliani’s quality factor Q [25-27], which is the ratio of This shows that hydrophobicity is another important
R and Se. parameter for the exhibition of the activity. It is
interesting to mention that in all the proposed models
The best three, four and five-parametric models, which
the coefficient of χeq is negative, while that of logP is
are most significant, are given below:
positive. This means that increase in the hydrophobicity
(i) Three-variable model(Model 14, Table-4) and decrease in the equalized electronegativity is
favourable for the exhibition of the activity. The
pIC50=-2.4300±(0.7833) Jhetp+0.4901±(0.1521) logP- proposed modelsshow that Balaban type indices also
6.1642±(1.2395) χeq+23.6746 support the exhibition of the activity. Their
negativecoefficients all over indicate that decrease in
N=34, R2=0.6156, R2A=0.5771, Se=0.0677, F=16.012, their magnitude favours exhibition of the activity.
Q=11.5847
It is interesting to mention that in all the above cases,
(ii) Four-variable model(Model 17, Table-4) both R2 and R2A goes on increasing with each addition
pIC50=-11.4322±(2.3692) Jhete-4.5078±(0.8445) of the correlating parameters. Naturally R2 will always
Jhetp+2.3568±(0.4961) 4χ-5.3358±(1.0854) χeq+33.1638 increase with each addition of correlating parameters.
However, R2A will increase if the added parameter is
N=34, R2=0.7332, R2A=0.6964, Se=0.0574, F=19.924, favourable for the exhibition of activity otherwise it
Q=14.9176 will decrease in our case. Since R2A goes on increasing
indicating that the added parameter is favorable for the
(iii) Five-variable model(Model 18, Table-4) exhibition of the activity.
pIC50=-9.6436±(2.2178) Jhete-4.0804±(0.7726) The best five-parametric model was used for estimating
4
Jhetp+0.3416±(0.1207) logP+2.1044±(0.4540) χ- the pIC50 value of training set. Such values are reported
5.2982±(0.9741) χeq + 28.6878 in Table 5. The predictive potential of this model has
been obtained by plotting a graph between observed
N=34, R2=0.7926, R2A=0.7555, Se=0.0515, F=21.399,
pIC50 and estimated pIC50 values. Such correlation is
Q=17.2870
depicted in Fig. 1.
1. When 4ᵡ is added to three-variable model, then the
To validate the model cross validation parameters have
value of R2 shows significant improvement. Also
been calculated and they are reported in Table 6. It is an
the adjusted R2 value changes from 0.5771 to
established fact that PRESS is a good estimate of the
0.6964, suggesting that the addition of 4ᵡis
real predictive power of the model. If PRESS is smaller
favourable.
than SSY, the model predicts better than chance and
can be considered statistically significant. Table 6
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International Journal of Trend in Scientific Research and Development (IJTSRD) ISSN: 2456-6470
shows that in this regard, all the models proposed by us Table 1: Structural details of compounds used in the
are better than chance and are statistically significant. present study.
The ratio PRESS SSY can be used to calculate the
X N NH
approximate confidence interval of the prediction of
new compounds. To be a reasonably good QSAR R1
model, this ratio should be smaller than 0.4. The N N
models proposed by us are having this ratio smaller N
than 0.4 and therefore, the model-18 has excellent R2
predictive power. The developed models are cross-
validated by leave-one-out method. Another cross- Compd. R1 X R2
validated parameter related to uncertainty of prediction, 1 2,4-diCl CH2 NH2
the PSE, has also been calculated. The lowest value of
2 2,4,6-triCl CH2 NH2
PSE for model 18 supports its highest predictive
potential (power).The low value of PSE and SPRESS and 3 2,4,6-triMe CH2 NH2
high value of R2CV suggest that the five-parametric *4 2,6diCl CH2 Cl
model is most appropriate in predicting pIC50 value of 5 2,6diCl CH2 NHMe
present set of compounds. 6 2,6diCl CH2 NMe2
This model was further validated by estimation of pIC 50 7 2,6diCl CH2 NHOMe
value for the test set. The results are reportedin Table 7. *8 2,6diCl CH2 NHOEt
A close look at this table reveals that estimated 9 2,6diCl CH2 SMe
activities are in good agreement with the observed
10 2,6diCl CH2 SH
activities. Hence, model 18 can be used for modeling
the pIC50 activity of present set of compounds. The 11 2,6diCl CH2 OMe
correlation potential for the test set is 0.835, which is *12 2,6diCl CH2 OH
better than the correlation potential of the training set. 13 2,6diCl CH2 F
14 2,4,6-triMe NH H
Conclusions:
15 2,6-diMe-4-Me NH H
Following conclusions may be drawn. *16 2,6-diMe-4-Br NH H
1. The topological indices in combination with 17 2,6-diMe-4-CN NH H
equalized electronegativity are best suitable for 18 2,4,6-triMe O H
modeling the anti HIV activity of present set of 19 2,4,6-triMe S H
compounds.
*20 2,4,6-triMe S NH2
2. Topological indices alone are not able to model the 21 2,6-diMe O NH2
biological activity in present set of compounds. 22 2,6-diMeO O NH2
3. Negative coefficients of Balaban type indices 23 2,4,6-triCl O NH2
suggest that they have retarding effect towards the
*24 2,4,6-triBr O NH2
pIC50 values, hence in future designing of potent
compounds their lower values will give results. 25 2,6-diCl-4-F O NH2
4. Higher value of logP will favour the activity as its 26 2,6-diBr-4-Me O NH2
coefficient is positive in the model.
27 2,6-diMe-4-Br O NH2
5. Due to negative coefficient of ᵡeq, lowelectronegativity *28 2,6-diMe-4-Cl O NH2
value will enhance the biological activity.
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International Journal of Trend in Scientific Research and Development (IJTSRD) ISSN: 2456-6470
X N NH
N
F
N
R1 F
N Cl
F
O N NH
N NH
N N
N N N
R2 39 N H2
H 2N
N N
H3C
29 2,4,6-triMe NH H
CH3 CH3
H 3C H 3C
30 2,6-diMe-4-CN O H O N NH S N
N N N
41
31 2,6-diMe-4-Br O H 42
N
*32 2,6-diMe-4-Br S H Br
H3C
33 2,4,6-triMe O H CH3
Cl Br
O N NH Br
O N N
34 2,4-diBr-6-F NH H N N
N N
NH2 43
35 2,4,6-triCl NH H *44
N
*36 2,6-diCl-6-Me NH H H3C
37 2,6-diBr-4-Me NH H CH3
H3C
NH N NH
38 2,6-diMe-4-Br NH H N N
45 NH2
*40
Table 2.Calculated values of the topological parameters for the compounds used in the present study with
equalizedelectronegativity values and their experimental pIC50 values
4
Compd. pIC50 Jhetp Jhete χ logP χeq
No.
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* Test set
pIC50 1.0000
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International Journal of Trend in Scientific Research and Development (IJTSRD) ISSN: 2456-6470
Table 4.Regression parameters and quality of correlation of training set
4
2 χ 0.8480±(0.6237) 2.0823 0.0251 0.0546 0.0251 1.848 9.3094
4
7 χ 1.0213±(0.4938) 17.0517 0.0812 0.4295 0.3927 11.670 8.0710
χeq -6.6968±(1.4837)
χeq -6.5212±(1.4089)
χeq -6.0923±(1.4011)
Jhete 1.5333±(1.8988)
logP 0.5263±(0.1749)
Jhetp -5.1418±(1.1110)
4
χ 2.6533±(0.6555)
χeq -6.6805±(1.3849)
Jhetp -3.5538±(1.0754)
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International Journal of Trend in Scientific Research and Development (IJTSRD) ISSN: 2456-6470
χeq -5.9629±(1.4125)
χeq -6.3307±(1.3147)
logP 0.4901±(0.1521)
χeq -6.1642±(1.2395)
Jhetp -3.1240±(0.9727)
logP 0.4514±(0.1545)
χeq -5.8245±(1.2638)
logP 0.4911±(0.1471)
4
χ 0.7260±(0.4133)
χeq -6.3240±(1.2020)
Jhetp -4.5078±(0.8445)
4
χ 2.3568±(0.4961)
χeq -5.3358±(1.0854)
Jhetp -4.0804±(0.7726)
logP 0.3416±(0.1207)
4
χ 2.1044±(0.4540)
χeq -5.2982±(0.9741)
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International Journal of Trend in Scientific Research and Development (IJTSRD) ISSN: 2456-6470
Table 5: Observed and estimated values of pIC50 (training set) using model no 18
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International Journal of Trend in Scientific Research and Development (IJTSRD) ISSN: 2456-6470
Table 6: Cross validation parameters for the proposed models
y = 0.7973x + 1.6994
9 R² = 0.7972
Est.pIC50
5
5.2 7.2 9.2
Obs.pIC50
Figure 1: Correlation between observed and estimated pIC 50 using training set (model 18)
Table 7: Observed and estimated values of pIC50 of test set molecules using model 18
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International Journal of Trend in Scientific Research and Development (IJTSRD) ISSN: 2456-6470
Figure 3.Correlation between observed and estimated pIC50 of test set by external cross validation using model 18
9.50
y = 0.4906x + 4.4386
R² = 0.8359
8.50
Est.pIC50
7.50
6.50
5.50
5.90 6.90 7.90 8.90
Obs.pIC50
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International Journal of Trend in Scientific Research and Development (IJTSRD) ISSN: 2456-6470
17. V.K. Agrawal, P.V. Khadikar, Bioorg. Med.Chem., 24. L. Pogliani, AminoAcids, 1994,6, 141.
2001, 9, 3035.
25. L. Pogliani, J.Phys. Chem., 1996, 100, 18065.
18. A. T. Balaban, Theor. Chem. Acta., 1979, 53, 355.
26. L. Pogliani, Chem. Rev., 2000,100, 3827.
19. A. T. Balaban, Pure & Appl. Chem., 198355, 199.
ACKNOWLEDGEMENT:
20. A. T. Balaban, Chem. Phy. Letts.1982, 89, 399.
21. M. Randić, J. Am. Chem. Soc., 1975,97, 6609. Authors are thankful to Late. Prof. P.V. Khadikar, Prof.
V. K. Agrawal, and Dr. Bashirulla Shaik for their
22. A. Leo,C. Hansch,D. Elkins, "Partition coefficients
guidance and support
and their uses", Chem. Rev.,1971,6, 525.
23. Sangster, James, Octanol-Water Partition
Coefficients: Fundamentals and Physical
Chemistry, Vol. 2 of Wiley Series in Solution
Chemistry, Chichester John Wiley & Sons Ltd,
1997.
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