1. Mechanism of Interaction of Novel Indolylarylsulfone Derivatives with K103N and Y181I Mutant HIV-1 Reverse Transcriptase in Complex with its Substrates
- Author
-
Francesco Piscitelli, Alberta Samuele, Giuseppe La Regina, Giovanni Maga, Romano Silvestri, Sara Bisi, Alexandra Kataropoulou, and Valerio Gatti
- Subjects
Models, Molecular ,Drug ,Anti-HIV Agents ,media_common.quotation_subject ,Mutant ,High selectivity ,Human immunodeficiency virus (HIV) ,Biology ,medicine.disease_cause ,Substrate Specificity ,Structure-Activity Relationship ,Drug Resistance, Viral ,medicine ,Humans ,Sulfones ,media_common ,chemistry.chemical_classification ,General Medicine ,Drug resistant mutants ,Molecular biology ,HIV Reverse Transcriptase ,Reverse transcriptase ,inhibitors NNRTIs ,Enzyme ,chemistry ,Docking (molecular) ,Mutation ,HIV-1 ,Reverse Transcriptase Inhibitors ,reverse transcriptase inhibitors - 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.
- Published
- 2011