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

NAG-thiazoline (NGT) and its derivatives are well-known inhibitors against most beta-acetylglucosaminidases (beta-GlcNAcases) except for insect and bacterial chitinolytic beta-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 K-i value of 0.13 mu M, which is 600-fold lower than K-i value of NGT. Molecular dynamics simulation analysis supported the good fit of NMAGT to the active pocket. (C) 2014 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.