Virtual Screening Identifies Chebulagic Acid as an Inhibitor of the M2(S31N) Viral Ion Channel and Influenza A Virus

Figures

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  Figure 1. (A) Chemical structures of amantadine and rimantadine. (B,C) M2(S31N) inhibitors assembled for VS and determination of shared pharmacophores. Inhibitors were grouped into adamantine (B) and non-adamantane (C)-class inhibitors.

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  Figure 2. (A,B) Alignment of adamantane-class inhibitors (A) and non-adamantane-class inhibitors (B). Chemical moieties that define shared pharmacophores are highlighted. (C) Structures of three p-ANAPL molecules identified with pharmacophores shown in A,B. (D) Structures of five marine and terrestrial natural product molecules with shared pharmacophores. For each compound, the identified RMSD value is shown.

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  Figure 3. Ability of compounds to restore growth in yeast expressing M2. (A,B) Restoration of yeast growth in M2(S31N) (A) and M2(S31)-expressing cells (B) in the presence of the control M2(S31N) inhibitor M2WJ352 and control M2(S31) inhibitor amantadine. (C,D) restoration of yeast growth in M2(S31N) (C) and M2(S31)-expressing cells (D) in the presence of natural products shown in Figure 2 (compounds 9–16). Effects of chebulagic acid are highlighted in green.

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  Figure 4. Summary of the expected hydrolysis fragments of chebulagic acid (P1 and P2) used for molecular modelling.

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  Figure 5. Relative 2D protein-ligand interaction maps of P1 and P2 into M2(S31N) and M2(S31). For each panel, the proposed ligand-protein interactions, amino acids and M2 subunit (A−D) are described as follows; green arrows are H-bond acceptors, blue arrows are H-bond donors, and green lines are π-π and cation-π interactions.

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  Figure 6. 3D pictures of protein-ligand interactions between P1 and P2 into M2(S31N) and M2(S31). For each panel, the proposed ligand-protein interactions, amino acids and M2 subunit (A−D) are labelled, with H-bonds shown as pink broken lines.