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

Slow Binding-Tight Binding Interaction Between benzimidazol-2-one Inhibitors and HIV-1 Reverse Transcriptase Containing the Lysine 103 to Asparagine Mutation

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Slow Binding-Tight Binding Interaction Between benzimidazol-2-one Inhibitors and HIV-1 Reverse Transcriptase Containing the Lysine 103 to Asparagine Mutation

Alberta Samuele et al. Antiviral Res. .

Abstract

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.

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