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

Abstract

AbstractConsidering 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 physico‐chemical parameters like hydrophobicity (π), electronic (Hammett σ) 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.