Indolyl aryl sulphones as HIV-1 reverse transcriptase inhibitors: docking and 3D QSAR studies

Indolyl aryl sulphones (IASs) are a potent class of HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs) developed from early studies on pyrryl aryl sulphones and pyrrolobenzothiadiazepines and correlated with Merck's compound L-737,126. This review focuses on how molecular modelling studies, refined structure-based drug design (SBDD) and ligand-based drug design (LBDD) guided the activity prediction, synthesis and biological evaluation of new potent and selective IASs. In particular, the binding mode analysis (SBDD) and three-dimensional quantitative structure activity relationship (3D QSAR) models (LBDD) are discussed, and their use is elucidated in design projects. Both SBDD and LBDD studies have led to the disclosure of subnanomolar active compounds. These compounds are revealed to be active against the most clinically relevant HIV-1 mutant strains and some drug-resistant clinical-isolated strains.