Exploring NAG-thiazoline and its derivatives as inhibitors of chitinolytic β-acetylglucosaminidases

FEBS Lett. 2015 Jan 2;589(1):110-6. doi: 10.1016/j.febslet.2014.11.032. Epub 2014 Nov 29.

Abstract

NAG-thiazoline (NGT) and its derivatives are well-known inhibitors against most β-acetylglucosaminidases (β-GlcNAcases) except for insect and bacterial chitinolytic β-GlcNAcases, including the molting-indispensable OfHex1 from the insect Ostrinia furnacalis. Here, we report the co-crystal structure of OfHex1 in complex with NGT. This structure reveals a large active pocket in OfHex1 that may account for the poor inhibitory activity of NGT. To test this hypothesis, a bulky substituent was designed and synthesized on the thiazoline ring of NGT. The resulting compound (NMAGT) was determined to be a submicromolar inhibitor of OfHex1 with a Ki value of 0.13 μM, which is 600-fold lower than Ki value of NGT. Molecular dynamics simulation analysis supported the good fit of NMAGT to the active pocket.

Keywords: Chitinolytic enzyme; Inhibitor; NGT; β-Acetylglucosaminidase.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylglucosamine / analogs & derivatives*
  • Acetylglucosamine / chemistry
  • Acetylglucosaminidase / antagonists & inhibitors
  • Acetylglucosaminidase / chemistry*
  • Animals
  • Enzyme Inhibitors / chemistry*
  • Insect Proteins* / antagonists & inhibitors
  • Insect Proteins* / chemistry
  • Molecular Dynamics Simulation
  • Moths / enzymology*
  • Thiazoles / chemistry*

Substances

  • Enzyme Inhibitors
  • Insect Proteins
  • Thiazoles
  • Acetylglucosaminidase
  • N-acetylglucosamine thiazoline
  • Acetylglucosamine