Computational modeling studies on anti-HIV-1 non-nucleoside reverse transcriptase inhibition by dihydroalkoxybenzyloxopyrimidines analogues: an electrotopological atomistic approach — Oak Academic Publishing
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Computational modeling studies on anti-HIV-1 non-nucleoside reverse transcriptase inhibition by dihydroalkoxybenzyloxopyrimidines analogues: an electrotopological atomistic approach
Department of Applied Chemistry, SGSITS, Indore, MP, INDIA
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1 Department of Applied Chemistry, SGSITS, Indore, MP, INDIA
For the first time we report quantitative structure activity relationship (QSAR) studies based on Kier-Hall Electrotopological State (E-State) Indices for Dihydroalkoxybenzyloxopyrimidines (DABO) derivatives acting as NNRTIs of HIV-1. A dataset of 74 compounds was compiled from published studies and randomly subdivided into training and test sets. To understand the pharmacophoric effect, Kier-Hall Electrotopological State descriptors namely S<sub>N1</sub>, S<sub>N3</sub>, S<sub>F</sub>, S<sub>Ar</sub>, S<sub>S</sub>, S<sub>O</sub>, S<sub>NO2</sub>, S<sub>Cl</sub>, S<sub>Y</sub> (Y = S-alkyl and NH-alkyl), S<sub>X</sub> (X = Me) and biological activity were used as independent and dependent variable respectively. Statistical results were highly encouraging for the training set multiple linear regression [(MLR): r<sup>2</sup> = 0.961, F = 100.41 and q<sup>2</sup> = 0.926, neural networks (NN): r<sup>2</sup> = 0.966, F = 115.594, degrees of freedom = 40 and k-nearest neighbour (k-NN): r<sup>2</sup> = 0.770, q<sup>2</sup> = 0.757, degrees of freedom = 40]. Results of validation using a test set showed the same trend as training set (NN > MLR > kNN). The above results suggest that of various functional groups present in DABO such as S<sub>N3</sub>, S<sub>O</sub>, S<sub>Cl</sub>, S<sub>Ar</sub> and S<sub>NO2</sub> contribute more significantly towards activity. On the other hand S<sub>N1</sub>, S<sub>S</sub>, and S<sub>F</sub> do not play any role in enhancing the activity. The substitution of S-alkyl and NH-alkyl at C<sub>2</sub> position is essential though it does not contribute much towards the activity. The substitution of methyl group at C<sub>5</sub> position is unfavorable and exhibit negative impact on inhibitory activity. Therefore, it seems reasonable to choose E-state indices as suitable and significant descriptors for exploring the relationship between the pIC<sub>50</sub> and the pharmacological properties of the compounds.
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Kier Hall E-State Indices
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