Symmetric, dimeric, BMS-790052 (Daclatasvir) 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 propose symmetric binding modes relative to the homodimeric target; however, none can fully explain SAR details for this class. We present a sequence-based, semi-automated workflow to model multiple receptor conformations for docking. Surprisingly, ranking receptors/hits with our library-derived 3D-pharmacophore revealed two distinct asymmetric binding modes, at a conserved poly-proline region between 31/93, 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. We use the same method to dock and model interactions of compounds with different scaffolds from Gilead, AbbVie, Merck/Idenix, and BMS. These detailed interaction models and proposed mechanisms of action will allow structure-based design of new NS5A targeted compounds with higher barriers to HCV resistance.

Structural informatics modeling of Daclatasvir and analogs reveals asymmetric binding to HCV-NS5A: Dual mechanisms responsible for picomolar activity and acquired resistance

249th National Meeting (2015)

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