Classical QSAR Modeling of HIV‐1 Reverse Transcriptase Inhibitor 2‐Amino‐6‐arylsulfonylbenzonitriles and Congeners

Abstract

Full PaperConsidering the recent interests in the development of novel and potent non-nucleoside reverse transcriptase inhibitors for the treatment of HIV-1 infection, anti-HIV-1 activity (assayed in MT-4 cell line) and HIV-1 reverse transcriptase (RT) binding affinity of 2-amino-6-arylsulfonylbenzonitriles and their thio and sulfinyl congeners (Chan et al., J. Med. Chem., 2001, 44, 1866 ± 1882 have been modeled using classical Quantitative Structure-Activity Relationship (QSAR) tools in an attempt to explore the quantitative contribution pattern of different substituents in the aryl ring to the activities. Different physicochemical parameters like hydrophobicity (p), electronic (Hammett s) and steric (molar refractivity MR) terms have been used along with appropriate indicator and/or integer variables to develop linear free energy related (LFER) model. Additionally, electrostatic potential point charges at different common atoms of the molecules calculated from AM1 optimized energy minimized geometry have also been tried as predictor variables. The models generated were of acceptable statistical quality and predictive potential. The results show that for both response variables, presence of sulfone moiety contributes significantly to the activities. Further, molar refractivity of meta substituents plays a significant role in both the cases: second meta substituents potentiate the activities probably due to enhanced binding (presumably through dispersion interaction) of the ligand with the binding site. Again, presence of meta-trifluoromethyl group at the aryl ring is detrimental for both the activities. Additionally, the anti-HIV-1 model shows negative contribution of the steric parameter of para substituents and positive contribution of the ortho-methoxy group.

Augmented Three‐mode MIA‐QSAR Modeling for a Series of Anti‐HIV‐1 Compounds

“…Also, our results supplant the ones obtained through a classical QSAR modeling, whose leave-10%-out crossvalidations ranged from 0.70 to 0.77 [12].…”

“…It was used in a recent MIA -QSAR study on anti-HIV-1 compounds [10], a series of 2-amino-6-arylsulfonylbenzonitriles, and the corresponding thio-and sulfinyl analogues, giving correlation results of experimental versus fitted/predicted activities comparable to a traditional approach [12]. In order to carry out the PLS regression, the three-way array built had to be unfolded to a two-way array.…”

“…Optimization starts with a backpropagation function which is solved by the nonlinear Levenberg -Marquardt algorithm [14]. These techniques were applied to the same series of 2-amino-6-arylsulfonylbenzonitriles and their thio-and sulfinyl con-geners ( Figure 1) were used elsewhere [10,12] in order to obtain models significantly superior than those currently available and to suggest alternatives to be incorporated in the MIA -QSAR method.…”

Comparative Classical QSAR Modeling of Anti‐HIV Thiocarbamates

“…The present group of authors has developed a few Quantitative Structure -Activity Relationship (QSAR) models for anti-HIV activities of different group of compounds, e.g., arylsulfonylbenzonitriles [10,11], alkenyldiarylmethanes [12], benzylpyrazoles [13], thiazolidinones [14], imidazoles [15,16], phenylpropylamines [17], mannitols [18], piperidinyl amides, and ureas [19]. In continuation of such efforts, the present paper deals with QSAR modeling of cytoprotection activity data of substituted thiocarbamates [20].…”

Quantitative Structure–Activity Relationship Analysis of Some Thiourea Derivatives with Activities Against HIV‐1 (IIIB)

“…AIDS has been recognized as a fatal pathogenic disease caused by a retrovirus of the lentivirus family, Human Immunodeficiency Virus (HIV) [3]. The number of HIV-infected subjects keeps alarmingly on the rise [4,5]. The pandemic spread of this disease has prompted an unprecedented scientific and clinical effort to understand and combat it [2,6].…”