Asymmetric Binding to NS5A by Daclatasvir (BMS-790052) and Analogs Suggests Two Novel Modes of HCV Inhibition

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• 作者：James H. Nettles ; Richard A. Stanton ; Joshua Broyde ; Franck Amblard ; Hongwang Zhang ; Longhu Zhou ; Junxing Shi ; Tamara R. McBrayer ; Tony Whitaker ; Steven J. Coats ; James J. Kohler ; Raymond F. Schinazi
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：December 11, 2014
• 年：2014
• 卷：57
• 期：23
• 页码：10031-10043
• 全文大小：886K
• ISSN：1520-4804

文摘

Symmetric, dimeric daclatasvir (BMS-790052) is the clinical lead for a class of picomolar inhibitors of HCV replication. While specific, resistance-bearing mutations at positions 31 and 93 of domain I strongly suggest the viral NS5A as target, structural mechanism(s) for the drugs鈥?activities and resistance remains unclear. Several previous models suggested symmetric binding modes relative to the homodimeric target; however, none can fully explain SAR details for this class. We present semiautomated workflows to model potential receptor conformations for docking. Surprisingly, ranking docked hits with our library-derived 3D-pharmacophore revealed two distinct asymmetric binding modes, at a conserved poly-proline region between 31 and 93, consistent with SAR. Interfering with protein鈥損rotein interactions at this membrane interface can explain potent inhibition of replication鈥揷omplex formation, resistance, effects on lipid droplet distribution, and virion release. These detailed interaction models and proposed mechanisms of action will allow structure-based design of new NS5A directed compounds with higher barriers to HCV resistance.