Figure 6. Molecular modelling of CCZ binding to HCV E1 protein.

A. Predicted binding model of (S)-CCZ with E1. The (S)-CCZ fits into a hydrophobic pocket of the space-filling model of E1 on the left. On the right, interactions of (S)-CCZ with various key amino acid residues, as identified by the mutagenesis studies, are shown in a ribbon model. The hydrogen bond between Q289 and the N atom of the piperazine, and a halogen bond between Q215 and the chlorophenyl group of (S)-CCZ provide significant stabilization. B. EC₅₀ values and predicted binding energies of CCZ analogs. The EC₅₀ values of 10 structurally related CCZ analogs published previously were compared with their respective predicted binding energies. C. The EC₅₀’s of 10 CCZ analogs (A) were plotted against their respective binding energies predicted based on various intermolecular interactions (e.g., hydrogen bonds, electrostatic interactions, pi-pi stacking, etc.). The anti-HCV activities of the CCZ analogs correlate well with the binding energies (R² = 0.7815, P = 0.0007).