Mechanism of Interaction of Novel Indolylarylsulfone Derivatives with K103N and Y181I Mutant HIV-1 Reverse Transcriptase in Complex with its Substrates

Abstract

Background: Novel indolylarylsulfones (lASs), designed through rational structure-based molecular modelling and docking approaches, have been recently characterized as effective inhibitors of the wild-type and drug-resistant mutant HIV-1 reverse transcriptase (RT). Methods: Here, we studied the interaction of selected halo- and nitra-substituted IAS derivatives, with the RT enzyme carrying the single resistance mutations K103N and Y181I through steady-state kinetic experiments. Results: The studied compounds exhibited high selectivity to the mutant RT in complex with its substrates, behaving as uncompetitive inhibitors. The presence of the K103N mutation, and to a lesser extent the Y181I, stabilized the drug interactions with the viral RT, when both its substrates were bound. Conclusions: The characterization of these mutation-specific effects on inhibitor binding might be relevant to the design of more effective new generation non-nucleoside reverse transcriptase inhibitors, with better resilience towards drug resistant mutants.