Ligand based 3D-QSAR modelling studies on 2-amino-6-aryl sulfonylbenzonitriles (AASBNs) as non-nucleoside reverse transcriptase inhibitors of HIV-1

Abstract

Non-nucleoside reverse transcriptase inhibitors (NNRTIs) have shown a lot of promise, yet their use has been limited in treating HIV-1 infection. In order to improve low treatment success rates, owing to the resistance developed, cross-resistance derived from mutational changes and fatal side-effects, modified and novel NNRTIs with better pharmacokinetic efficacies are required. In an effort to design novel NNRTIs, we report 3D structure–activity relationship (SAR) quantifying pharmacophoric descriptors (S_ALL, HD_ALL, HA_ALL, R_ALL and POS_ALL), generated from the similarity based alignment of molecules with respect to the group centre overlap from each individual template point. The 3D pharmacophore based mapping of the compounds and subsequent comparison with respect to the bridging groups S/SO/SO₂ and the substituents on rings ‘A’ and ‘B’ yielded good results. Also, statistical modeling of the 3D structural parameters was performed on the aforementioned series, with noteworthy results (ANN: r² = 0.914, MLR: r² = 0.902). The findings were well-reciprocated while cross-validating using a test-set (ANN: r² = 0.855, MLR: r² = 0.805). These findings and analyses warrant further development of these series of compounds to enhance their medicinal application for the treatment of AIDS in both NNRTI-experienced and -naïve patients.