Importance of Ligand Bioactive Conformation in the Discovery of Potent Indole-Diamide Inhibitors of the Hepatitis C Virus NS5B

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• 作者：Steven R. LaPlante ; James R. Gillard ; Araz Jakalian ; Norman Aubry ; Ren Coulombe ; Christian Brochu ; Youla S. Tsantrizos ; Martin Poirier ; George Kukolj ; Pierre L. Beaulieu
• 刊名：Journal of the American Chemical Society
• 出版年：2010
• 出版时间：November 3, 2010
• 年：2010
• 卷：132
• 期：43
• 页码：15204-15212
• 全文大小：467K
• 年卷期：v.132,no.43(November 3, 2010)
• ISSN：1520-5126

文摘

Significant advances have led to receptor induced-fit and conformational selection models for describing bimolecular recognition, but a more comprehensive view must evolve to also include ligand shape and conformational changes. Here, we describe an example where a ligand’s “structural hinge” influences potency by inducing an “L-shape” bioactive conformation, and due to its solvent exposure in the complex, reasonable conformation-activity-relationships can be qualitatively attributed. From a ligand design perspective, this feature was exploited by successful linker hopping to an alternate “structural hinge” that led to a new and promising chemical series which matched the ligand bioactive conformation and the pocket bioactive space. Using a combination of X-ray crystallography, NMR and modeling with support from binding-site resistance mutant studies and photoaffinity labeling experiments, we were able to derive inhibitor-polymerase complexes for various chemical series.