Computational Modeling of Substitution Effect on HIV-1 Non-Nucleoside Reverse Transcriptase Inhibitors with Kier-Hall Electrotopological State (E-state) Indices

N Sapre, N Pancholi, S Gupta
2008 Computational Modeling of Substitution Effect on HIV-1 Non-Nucleoside Reverse Transcriptase Inhibitors Internet Electronic Journal of Molecular Design   unpublished
Motivation 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 Estate 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
more » ... he inhibitory activity of HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs). The applicability of Kier-Hall Estate indices can provide a new insight to the quantitative structure-activity relationship studies of potential drug compounds. Method. 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. Results. 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, R 2 = 0.711, R 2 adj = 0.638, R 2 pre = 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 Estate values are OCH 3 , CH 3 , CN (on ring B), Cl, Br, F and CN (on ring A) while with negative coefficient is NH 2. The Estate for the bridging atoms S, SO and SO 2 also showed different positive coefficients. The result of the test set too gave a good fit (n = 5, R = 0.897, R 2 = 0.804, R 2 adj = 0.738, R 2 pre = 0.239, SE = 0.301, SSE = 0.841, PRESS = 1.05, p-value = 0.0393, F-ratio = 12.30). Conclusions. A high positive coefficient for the cyano group on ring B (E CN-B) indicates that its presence will have a major contribution towards enhancing the inhibitory activity while a high negative coefficient for amino group (E NH2) 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 SO 2. Other substituents, owing to their smaller positive coefficients will have a lesser impact on the inhibitory activity. Thus, Kier-Hall Estate indices could be well applied in deriving QSAR models and analyzing the substitution effects. Keywords. Non nucleoside reverse transcriptase inhibitors; QSAR; quantitative structure-activity relationships; Kier-Hall electrotopological state indices; multiple linear regression. 55 BioChem Press