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

  • Samuele A
  • Crespan E
  • Vitellaro S
 et al. 
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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. © 2010 Elsevier B.V.

Author-supplied keywords

  • Antiretroviral therapy
  • Benzimidazolones
  • Drug resistant HIV-1 mutant
  • Non-nucleoside HIV-1 reverse transcriptase inhibitors

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  • Alberta Samuele

  • Emmanuele Crespan

  • Samanta Vitellaro

  • Anna Maria Monforte

  • Patrizia Logoteta

  • Alba Chimirri

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