Slow binding-tight binding interaction between benzimidazol-2-one inhibitors and HIV-1 reverse transcriptase containing the lysine 103 to asparagine mutation
Copyright 2010 Elsevier B.V. All rights reserved..
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2010 |
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| Erschienen: |
2010 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:86 |
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| Enthalten in: |
Antiviral research - 86(2010), 3 vom: 01. Juni, Seite 268-75 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Samuele, Alberta [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 06.08.2010 Date Revised 21.11.2013 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.antiviral.2010.03.008 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM196550238 |
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| 245 | 1 | 0 | |a 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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| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright 2010 Elsevier B.V. All rights reserved. | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 7 | |a Benzimidazoles |2 NLM | |
| 650 | 7 | |a Mutant Proteins |2 NLM | |
| 650 | 7 | |a Reverse Transcriptase Inhibitors |2 NLM | |
| 650 | 7 | |a benzimidazol-2-one |2 NLM | |
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| 700 | 1 | |a Crespan, Emmanuele |e verfasserin |4 aut | |
| 700 | 1 | |a Vitellaro, Samanta |e verfasserin |4 aut | |
| 700 | 1 | |a Monforte, Anna-Maria |e verfasserin |4 aut | |
| 700 | 1 | |a Logoteta, Patrizia |e verfasserin |4 aut | |
| 700 | 1 | |a Chimirri, Alba |e verfasserin |4 aut | |
| 700 | 1 | |a Maga, Giovanni |e verfasserin |4 aut | |
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