Illuminating the binding interactions of galactonoamidines during the inhibition of β-galactosidase (E. coli)
Glycosidase, Inhibition, H-bonding, Carbohydrate
Several galactonoamidines were previously identified as very potent competitive inhibitors that exhibit stabilizing hydrophobic interactions of the aglycon in the active site of β-galactosidase (Aspergillus oryzae). To elucidate the contributions of the glycon to the overall inhibition ability of the compounds, three glyconoamidine derivatives with alteration in the glycon at C-2 and C-4 were synthesized and evaluated herein. All amidines are competitive inhibitors of β-galactosidase (Escherichia coli) and show significantly reduced inhibition ability when compared to the parent. The results highlight strong hydrogen-bonding interactions between the hydroxyl group at C-2 of the amidine glycon and the active site of the enzyme. Slightly weaker H-bonds are promoted through the hydroxyl group at C-4. The inhibition constants were determined to be picomolar for the parent galactonoamidine, and nanomolar for the designed derivatives rendering all glyconoamidines very potent inhibitors of glycosidases albeit the derivatized amidines show up to 700-fold lower inhibition activity than the parent.
Fan, Q., Pickens, J. B., Striegler, S., & Gervaise, C. (2016). Illuminating the binding interactions of galactonoamidines during the inhibition of β-galactosidase (E. coli). Bioorganic & Medicinal Chemistry, 24(4), 661-671. doi:https://doi.org/10.1016/j.b