Figure 6. Characterization of shikimate kinase inhibitors by enzyme assay, CoreSiMMaps, site-mutagenesis studies, and analogues.

(A–C) Structures of three inhibitors, NSC162535 (2), NSC45611 (1), and NSC45612 (3). (D–F) Relationships between anchors and docked mode of each inhibitor for HpSK. These compounds consistently include two negative charge moieties (SO₃ ⁻ or CO₂ ⁻) that form hydrogen bonds with conserved interacting residues of anchors E1 and H1. (G) Comparison of relative activities of HpSK mutants. The conserved interacting residues for each anchor were mutated. R57, R132, R116, and F48 located in the shikimate site were critical for the enzymatic functions. (H) Potency of NSC162535 analogues. The substitution moieties of analogues are indicated in black. Those that lack the E1 moiety greatly lost the inhibitory effects (IC₅₀>100 µM).