Slow binding-tight binding interaction between benzimidazol-2-one inhibitors and HIV-1 reverse transcriptase containing the lysine 103 to asparagine mutation

Antiviral Res. 2010 Jun;86(3):268-75. doi: 10.1016/j.antiviral.2010.03.008. Epub 2010 Mar 20.


Novel benzimidazol-2-one non-nucleoside reverse transcriptase inhibitors (NNRTIs) have been recently identified, through rational structure-based molecular modeling and docking approaches, as highly effective inhibitors of the wild type and drug-resistant HIV-1 reverse transcriptase (RT). These compounds also showed potent anti-HIV activities against viral strains, superior to the clinically approved NNRTI efavirenz. However, they were still of limited efficacy towards the K103N mutant. Here we report a detailed enzymatic analysis elucidating the molecular mechanism of interaction between benzimidazol-2-one derivatives and the K103N mutant RT. The loss of potency of these molecules towards the K103N RT was specifically due to a reduction of their association rate to the enzyme. Unexpectedly, these compounds showed a strongly reduced dissociation rate from the K103N mutant, as compared to the wild type enzyme, suggesting that, once occupied by the drug, the mutated binding site could achieve a more stable interaction with these molecules. The characterization of this slow binding-tight binding mutant-specific mechanism of interaction may pave the way to the design of more effective new generation benzimidazol-2-one NNRTIs with promising drug resistant profile and minimal toxicity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Substitution / genetics*
  • Asparagine / genetics
  • Benzimidazoles / metabolism*
  • Cell Line
  • Cell Survival
  • HIV Reverse Transcriptase / metabolism*
  • HIV-1 / drug effects
  • Humans
  • Kinetics
  • Lysine / genetics
  • Microbial Sensitivity Tests
  • Models, Molecular
  • Molecular Structure
  • Mutant Proteins / metabolism
  • Mutation, Missense*
  • Protein Binding
  • Reverse Transcriptase Inhibitors / metabolism*


  • Benzimidazoles
  • Mutant Proteins
  • Reverse Transcriptase Inhibitors
  • benzimidazol-2-one
  • Asparagine
  • reverse transcriptase, Human immunodeficiency virus 1
  • HIV Reverse Transcriptase
  • Lysine