NMR line-broadening and transferred NOESY as a medicinal chemistry tool for studying inhibitors of the hepatitis C virus NS3 protease domain |
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Authors: | LaPlante S R Aubry N Bonneau P R Kukolj G Lamarre D Lefebvre S Li H Llinàs-Brunet M Plouffe C Cameron D R |
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Affiliation: | Department of Chemistry, Boehringer Ingelheim, Laval, Québec, Canada. slaplante@lav.boehringer-ingelheim.com |
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Abstract: | This work describes the use of NMR as a medicinal chemistry tool for better understanding the binding characteristics of inhibitors of the HCV NS3 protease. The protease-bound structure of a tetrapeptide-like inhibitor that has an acid C-terminus, a norvaline at P1 and a naphthylmethoxy proline at P2 is described. Conformational comparisons are made with a similar compound having a 1-amino-cyclopropylcarboxylic acid at P1 and with a hexapeptide inhibitor. Differences between the free and bound states are identified. 19F NMR also helped in determining that a single complex is observed when an inhibitor is added to the protease at a 1:1 ratio. |
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