Premium
Exploring NAG‐thiazoline and its derivatives as inhibitors of chitinolytic β‐acetylglucosaminidases
Author(s) -
Liu Tian,
Xia Meng,
Zhang Haitao,
Zhou Hao,
Wang Jing,
Shen Xu,
Yang Qing
Publication year - 2015
Publication title -
febs letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.593
H-Index - 257
eISSN - 1873-3468
pISSN - 0014-5793
DOI - 10.1016/j.febslet.2014.11.032
Subject(s) - thiazoline , ostrinia furnacalis , substituent , chemistry , active site , stereochemistry , enzyme , biochemistry , biology , botany , larva
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 K i value of 0.13 μM, 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.