Exploring isoxazole and carboxamide derivatives as potential non-nucleoside reverse transcriptase inhibitors

[Display omitted] •Benchmarking of softwares Dock and AutoDock Vina using two RT protein structures 2ZD1 and 1RT1 has been carried out.•Carboxamide pharmacophore based molecules yield better docking score compared to the oxazole based molecules.•A fluoro, a nitrile and an amide group are the positive contributors toward the activity of a molecule as NNRT inhibitor.•Basic NNRTI skeleton has a central triazine ring with aniline, a trimethylphenoxy group and a benzyl amide substituent. Nonnucleoside reverse transciptase inhibitors (NNRTI) are a class of drug molecules with a specific target of HIV-1 reverse transcriptase (RT). In the present work, we evaluated a set of selected oxazole and carboxamide derivatives to identify potential pharmacophoric features using molecular docking approach. The docking approach employed has been validated by enrichment factor calculation at top 1% (EF1%). It shows a considerable improvement in EF1%value compared to earlier reported study carried out on specific dataset of ligands and decoys for RT, in the directory of useful decoys (DUD). The carboxamide derivatives show better activity as NNRT inhibitors than oxazole derivatives. From this study, four pharmacophoric groups including a triazine ring, an aniline substituent, a benzyl amide moiety and a trimethylphenoxy substituent have been recognized and used for designing new NNRT inhibitors. Newly designed molecules show significant enhancement in docking scores over the native ligand, parent and other training set molecules. In addition, some functional groups have also been identified to assist in improving the activity of these pharmacophores. Thus a nitrile group, an amide and fluoro substitution turn out to be an important requisite for NNRT potential inhibitors.