title: 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 (IASs), 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 nitro-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.
authors.affiliation: Department of DNA Enzymology and Molecular Virology, Institute of Molecular Genetics-National Research Council, IGM-CNR, Pavia, Italy.
authors.forename: Alberta
authors.initials: A
authors.lastname: Samuele
authors.forename: Sara
authors.initials: S
authors.lastname: Bisi
authors.forename: Alexandra
authors.initials: A
authors.lastname: Kataropoulou
authors.forename: Giuseppe
authors.initials: G
authors.lastname: La Regina
authors.forename: Francesco
authors.initials: F
authors.lastname: Piscitelli
authors.forename: Valerio
authors.initials: V
authors.lastname: Gatti
authors.forename: Romano
authors.initials: R
authors.lastname: Silvestri
authors.forename: Giovanni
authors.initials: G
authors.lastname: Maga
mesh_terms: D019380:Anti-HIV Agents / Q000737:chemistry / Q000494:pharmacology*; D024882:Drug Resistance, Viral / Q000187:drug effects; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D015497:HIV-1 / Q000187:drug effects / Q000201:enzymology*; D006801:Humans; D008958:Models, Molecular; D009154:Mutation / Q000235:genetics*; D018894:Reverse Transcriptase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D013450:Sulfones / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D019380:Anti-HIV Agents; D018894:Reverse Transcriptase Inhibitors; D013450:Sulfones; C514824:reverse transcriptase, Human immunodeficiency virus 1; D054303:HIV Reverse Transcriptase