Identification of lead small molecule inhibitors of glycogen synthase kinase-3 beta using a fragment-linking strategy

Cited 9 time in webofscience Cited 0 time in scopus
  • Hit : 388
  • Download : 0
Glycogen synthase kinase-3 beta (GSK3b) kinase serves as a promising therapeutic target for the treatment of various human diseases, such as diabetes, obesity, and Alzheimer's disease. In this study, we report lead GSK3 beta inhibitors identified using a fragment-linking strategy. Through the systematic exploration, a six-atom chain unit bearing the rigid double bond was found to be a suitable linker connecting two fragments, which enables favorable contacts with backbone groups of residues in the pockets. As a consequence, potent GSK3 beta inhibitor 9i was found with IC50 values of 19 nM. The binding mode analysis indicates that the activities of the inhibitors appear to be achieved by the establishment of multiple hydrogen bonds and hydrophobic interactions in the ATP-binding site of GSK3 beta . The good biochemical potencies and structural uniqueness of the inhibitors support consideration in the further study to optimize the biological activity. (C) 2016 Elsevier Ltd. All rights reserved.
Publisher
PERGAMON-ELSEVIER SCIENCE LTD
Issue Date
2016-12
Language
English
Article Type
Article
Keywords

POTENT INHIBITORS; WILD-TYPE; IN-VIVO; GSK-3-BETA INHIBITORS; BRAIN PERMEABILITY; GSK3 INHIBITORS; DUAL INHIBITORS; DRUG DISCOVERY; PROTEIN-KINASE; T315I MUTANT

Citation

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, v.26, no.23, pp.5669 - 5673

ISSN
0960-894X
DOI
10.1016/j.bmcl.2016.10.060
URI
http://hdl.handle.net/10203/216127
Appears in Collection
CH-Journal Papers(저널논문)
Files in This Item
There are no files associated with this item.
This item is cited by other documents in WoS
⊙ Detail Information in WoSⓡ Click to see webofscience_button
⊙ Cited 9 items in WoS Click to see citing articles in records_button

qr_code

  • mendeley

    citeulike


rss_1.0 rss_2.0 atom_1.0