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Binding Mode Determination of Benzimidazole Inhibitors of the Hepatitis C Virus RNA Polymerase by a Structure and Dynamics Strategy

Authors

  • Steven R. LaPlante Dr.,

    1. Departments of Chemistry and Biological Sciences, Boehringer Ingelheim, Canada, Ltd., Research and Development, 2100 Cunard St., Laval, Quebec, Canada, H7S2G5, Fax: (+1) 450-682-8434
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  • Araz Jakalian,

    1. Departments of Chemistry and Biological Sciences, Boehringer Ingelheim, Canada, Ltd., Research and Development, 2100 Cunard St., Laval, Quebec, Canada, H7S2G5, Fax: (+1) 450-682-8434
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  • Norman Aubry,

    1. Departments of Chemistry and Biological Sciences, Boehringer Ingelheim, Canada, Ltd., Research and Development, 2100 Cunard St., Laval, Quebec, Canada, H7S2G5, Fax: (+1) 450-682-8434
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  • Yves Bousquet,

    1. Departments of Chemistry and Biological Sciences, Boehringer Ingelheim, Canada, Ltd., Research and Development, 2100 Cunard St., Laval, Quebec, Canada, H7S2G5, Fax: (+1) 450-682-8434
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  • Jean-Marie Ferland,

    1. Departments of Chemistry and Biological Sciences, Boehringer Ingelheim, Canada, Ltd., Research and Development, 2100 Cunard St., Laval, Quebec, Canada, H7S2G5, Fax: (+1) 450-682-8434
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  • James Gillard,

    1. Departments of Chemistry and Biological Sciences, Boehringer Ingelheim, Canada, Ltd., Research and Development, 2100 Cunard St., Laval, Quebec, Canada, H7S2G5, Fax: (+1) 450-682-8434
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  • Sylvain Lefebvre,

    1. Departments of Chemistry and Biological Sciences, Boehringer Ingelheim, Canada, Ltd., Research and Development, 2100 Cunard St., Laval, Quebec, Canada, H7S2G5, Fax: (+1) 450-682-8434
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  • Martin Poirier,

    1. Departments of Chemistry and Biological Sciences, Boehringer Ingelheim, Canada, Ltd., Research and Development, 2100 Cunard St., Laval, Quebec, Canada, H7S2G5, Fax: (+1) 450-682-8434
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  • Youla S. Tsantrizos,

    1. Departments of Chemistry and Biological Sciences, Boehringer Ingelheim, Canada, Ltd., Research and Development, 2100 Cunard St., Laval, Quebec, Canada, H7S2G5, Fax: (+1) 450-682-8434
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  • George Kukolj,

    1. Departments of Chemistry and Biological Sciences, Boehringer Ingelheim, Canada, Ltd., Research and Development, 2100 Cunard St., Laval, Quebec, Canada, H7S2G5, Fax: (+1) 450-682-8434
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  • Pierre L. Beaulieu

    1. Departments of Chemistry and Biological Sciences, Boehringer Ingelheim, Canada, Ltd., Research and Development, 2100 Cunard St., Laval, Quebec, Canada, H7S2G5, Fax: (+1) 450-682-8434
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  • We are grateful to Dr. Michael Bös, Dr. Michael Cordingley, and Dr. Paul Anderson for encouragement and support. We also thank Dr. Timothy Stammers, Dr. Nathalie Goudreau, Dr. Marc-André Poupart, Dr. Dale Cameron, and Mr. Jeff O'Meara for comments or critical reading of the manuscript, as well as Ginette McKercher for determining inhibition constants.

Abstract

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Eine neuartige Strategie, die NMR-Spektroskopie, medizinische Chemie und Molecular Modeling umfasst, diente zur Bestimmung der Bindungsweise von Liganden und der Rolle ihrer Substituenten dabei. Diese erste Lösungsstruktur eines an die Hepatitis-C-Virus(HCV)-Polymerase gebundenen Inhibitors (siehe Bild) liefert wertvolle Informationen für das rationale Design potenzieller Wirkstoffe gegen HCV-Infektionen.

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