Computational modeling studies on anti-HIV-1 non-nucleoside reverse transcriptase inhibition by dihydroalkoxybenzyloxopyrimidines analogues: an electrotopological atomistic approach

Nitin S. Sapre, Tarang Bhati, Swagata Gupta, Nilanjana Pancholi, Urmila Raghuvanshi, Divya Dubey, Vandana Rajopadhyay, Neelima Sapre

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Department of Applied Chemistry, SGSITS, Indore, MP, INDIA.

DOI: 10.4236/jbpc.2011.23041                

Abstract

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_N1, S_N3, S_F, S_Ar, S_S, S_O, S_NO2, S_Cl, S_Y (Y = S-alkyl and NH-alkyl), S_X (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): r² = 0.961, F = 100.41 and q² = 0.926, neural networks (NN): r² = 0.966, F = 115.594, degrees of freedom = 40 and k-nearest neighbour (k-NN): r² = 0.770, q² = 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_N3, S_O, S_Cl, S_Ar and S_NO2 contribute more significantly towards activity. On the other hand S_N1, S_S, and S_F do not play any role in enhancing the activity. The substitution of S-alkyl and NH-alkyl at C₂ position is essential though it does not contribute much towards the activity. The substitution of methyl group at C₅ 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 pIC₅₀ and the pharmacological properties of the compounds.

Keywords

AIDS; HIV-1; NNRTIs; DABOs; QSAR; pIC₅₀; Kier Hall E-State Indices; MLR; NN; k-NN

Conflicts of Interest

The authors declare no conflicts of interest.

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