Exploring substituent diversity on pyrrolidine-aryltriazole iminosugars: Structural basis of β-glucocerebrosidase inhibition.
Biocatalysis
Cell Line
Crystallography, X-Ray
Dose-Response Relationship, Drug
Enzyme Inhibitors
/ chemical synthesis
Glucosylceramidase
/ antagonists & inhibitors
Humans
Hydrophobic and Hydrophilic Interactions
Imino Sugars
/ chemical synthesis
Molecular Docking Simulation
Molecular Structure
Mutation
Pyrrolidines
/ chemistry
Structure-Activity Relationship
Surface Properties
Triazoles
/ chemistry
Chaperones
Click chemistry
Iminosugars
Protein crystallization
Pyrrolidines
Triazoles
β-glucocerebrosidase inhibitors
Journal
Bioorganic chemistry
ISSN: 1090-2120
Titre abrégé: Bioorg Chem
Pays: United States
ID NLM: 1303703
Informations de publication
Date de publication:
05 2019
05 2019
Historique:
received:
09
01
2019
revised:
05
02
2019
accepted:
09
02
2019
pubmed:
3
3
2019
medline:
14
4
2020
entrez:
3
3
2019
Statut:
ppublish
Résumé
The synthesis of a library of pyrrolidine-aryltriazole hybrids through CuAAC between two epimeric dihydroxylated azidomethylpyrrolidines and differently substituted phenylacetylenes is reported. The evaluation of the new compounds as inhibitors of lysosomal β-glucocerebrosidase showed the importance of the substitution pattern of the phenyl moiety in the inhibition. Crystallization and docking studies revealed key interactions of the pyrrolidine motif with aminoacid residues of the catalytic site while the aryltriazole moiety extended along a hydrophobic surface groove. Some of these compounds were able to increase the enzyme activity in Gaucher patient fibroblasts, acting as a new type of chemical chaperone for Gaucher disease.
Identifiants
pubmed: 30825709
pii: S0045-2068(19)30034-3
doi: 10.1016/j.bioorg.2019.02.025
pii:
doi:
Substances chimiques
Enzyme Inhibitors
0
Imino Sugars
0
Pyrrolidines
0
Triazoles
0
Glucosylceramidase
EC 3.2.1.45
pyrrolidine
LJU5627FYV
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
652-664Subventions
Organisme : NIA NIH HHS
ID : F32 AG027647
Pays : United States
Organisme : NEI NIH HHS
ID : R01 EY021205
Pays : United States
Informations de copyright
Copyright © 2019 Elsevier Inc. All rights reserved.