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

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

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 SN1, SN3, SF, SAr, SS, SO, SNO2, SCl, SY (Y = S-alkyl and NH-alkyl), SX (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 SN3, SO, SCl, SAr and SNO2 contribute more significantly towards activity. On the other hand SN1, SS, and SF 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.

Highlights

Acquired Immunodeficiency Syndrome (AIDS) is a set of symptoms and infections resulting from the damage of the human immune system caused by the human immunodeficiency virus (HIV) [1]
It records the inhibitory concentration pIC50 and the calculated E-State values (N1, N3, O, X, Y, Ar, S, F, Cl, and NO2) of various atoms or groups in the DABO analogues
From the above study related to Dihydroalkoxybenzyloxopyrimidines derivatives following conclusions can be drawn: The 2D-quantitative structure activity relationship (QSAR) studies indicated that the anti-HIV-1 activity of DABO derivatives was strongly dependent on the nature of the substituents at N1, N3, C2, C4, C5, and C6 of the pyrimidine ring

Summary

Introduction

Acquired Immunodeficiency Syndrome (AIDS) is a set of symptoms and infections resulting from the damage of the human immune system caused by the human immunodeficiency virus (HIV) [1]. An anti-HIV agent may exert its activity by inhibiting a variety of steps in the life cycle of the virus [3]. Reverse transcription is a highly choreographed, multistep process in which the plus-strand RNA genome of the HIV-1 is converted into a double-stranded cDNA [4]. HIV-1 reverse transcriptase (RT) is an asymmetric heterodimer composed of two related subunits, p66 (560 amino acids) and p51 (440 amino acids). P66 folds into two domains: polymerase and RNase H. Inhibitors of HIV-1 RT fall under two categories: the nucleoside (NRTIs) and the non-nucleoside reverse transcriptase

Methods

Results

Conclusion