Targeting the Motion of Shikimate Kinase: Development of Competitive Inhibitors that Stabilize an Inactive Open Conformation of the Enzyme

The
large conformational changes observed by Molecular Dynamics simulation
studies on the product release in the LID and shikimic acid binding
(SB) domains of the shikimate kinase (SK) enzyme have been exploited
in the development of reversible competitive inhibitors against SK
from Mycobacterium tuberculosis and Helicobacter pylori. This enzyme is a recognized
target for antibiotic drug discovery. The reported C5-substituted
shikimic acid analogues interact with the dynamic apolar pocket that
surrounds the C4 and C5 hydroxyl groups of the natural substrate,
cause the opening of the LID and SB domains, and capture the essential
arginine far from the ATP binding site as required for catalysis.
The 3-nitrobenzyl 3e and 5-benzothiophenyl derivatives 3i proved to be the most potent inhibitors. An ester prodrug
of 3i was the most efficient derivative in achieving
good in vitro activity against H. pylori, having a MIC value of 4 μg/mL.