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Internet Electronic Journal of Molecular Design - IEJMD, ISSN 1538-6414, CODEN IEJMAT
| ABSTRACT - Internet Electron. J. Mol. Des. March 2008, Volume 7, Number 3, 55-67 |
Computational Modeling of Substitution Effect on HIV-1 Non-Nucleoside Reverse
Transcriptase Inhibitors with Kier-Hall Electrotopological State (E-state) Indices
Nitin S. Sapre, Nilanjana Pancholi, and Swagata Gupta
Internet Electron. J. Mol. Des. 2008, 7, 55-67
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Abstract:
The application of Kier-Hall electrotopological state (E-state) indices has helped
in deriving mathematical models, where the electronic attributes of an atom in a
chemical graph could be encoded as an index. By changing a substituent in a
molecule, a corresponding change in its E-state value as well as
physicochemical/biological properties is observed. With the help of Kier-Hall
electrotopological indices, the effect of substituent could be analyzed and
subsequently used in modeling the inhibitory activity of HIV-1 non-nucleoside
reverse transcriptase inhibitors (NNRTIs). The applicability of Kier-Hall E-state
indices can provide a new insight to the quantitative structure-activity relationship
studies of potential drug compounds. The multiple linear regression (MLR)
method is used to generate a predictive model for the training set consisting of a
series of 55 derivatives of 2-amino-6-arylsulfonylbenzonitrile (AASBN). The
result is cross-validated with the help of a test set. A QSAR model for a series of
55 AASBN derivatives is generated to understand the effect of substitution on
their inhibitory activity (n = 55, R = 0.843,
R2 = 0.711, R2adj = 0.638,
R2pre = 0.468,
SE = 0.513, SSE = 0.865, PRESS = 20.83, p-value = 0.00, F-ratio = 9.64).
The functional groups with positive coefficient of E-state values are OCH3, CH3,
CN (on ring B), Cl, Br, F and CN (on ring A) while with negative coefficient is
NH2. The E-state for the bridging atoms S, SO and SO2 also showed different
positive coefficients. The result of the test set too gave a good fit (n = 5,
R = 0.897, R2 = 0.804, R2adj = 0.738,
R2pre = 0.239, SE = 0.301, SSE = 0.841, PRESS =
1.05, p-value = 0.0393, F-ratio = 12.30). A high positive coefficient for the cyano
group on ring B (ECN-B) indicates that its presence will have a major contribution
towards enhancing the inhibitory activity while a high negative coefficient for
amino group (ENH2) suggests that its presence will retard the inhibitory activity.
Among the halo substituents, Cl seemed to be more effective as compared to Br
and F. Also, S as a bridging atom will have a higher impact on enhancing the
inhibitory activity, followed by SO and SO2. Other substituents, owing to their
smaller positive coefficients will have a lesser impact on the inhibitory activity.
Thus, Kier-Hall E-state indices could be well applied in deriving QSAR models
and analyzing the substitution effects.
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