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

作者：Nettles James H^*; Stanton Richard A; Broyde Joshua; Amblard Franck; Zhang Hongwang; Zhou Longhu; Shi Junxing; McBrayer Tamara R; Whitaker Tony; Coats Steven J; Kohler James J; Schinazi Raymond F

来源：Journal of Medicinal Chemistry, 2014, 57(23): 10031-10043.

DOI：10.1021/jm501291c

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' 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-protein interactions at this membrane interface can explain potent inhibition of replication-complex 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.

• 出版日期2014-12-11