N,O-Dialkyl deoxynojirimycin derivatives as CERT START domain ligands.
1-Deoxynojirimycin
/ chemistry
Binding Sites
Ceramides
/ metabolism
Glucosamine
/ analogs & derivatives
Glycoside Hydrolases
/ antagonists & inhibitors
Humans
Ligands
Molecular Docking Simulation
Protein Binding
Protein Domains
Protein Serine-Threonine Kinases
/ chemistry
Stereoisomerism
Thermodynamics
CERT
Ceramide
Deoxynojirimycin
Iminosugar
Sphingolipid
Journal
Bioorganic & medicinal chemistry letters
ISSN: 1464-3405
Titre abrégé: Bioorg Med Chem Lett
Pays: England
ID NLM: 9107377
Informations de publication
Date de publication:
15 01 2020
15 01 2020
Historique:
received:
13
09
2019
revised:
17
10
2019
accepted:
30
10
2019
pubmed:
24
11
2019
medline:
23
1
2021
entrez:
24
11
2019
Statut:
ppublish
Résumé
Dysregulation of the ceramide transport protein CERT is associated to diseases such as cancer. In search for new CERT START domain ligands, N-dodecyl-deoxynojirimycin (N-dodecyl-DNJ) iminosugar was found to display, as a ceramide mimic, significant protein recognition. To reinforce the lipophilic interactions and strengthen this protein binding, a docking study was carried out in order to select the optimal position on which to introduce an additional O-alkyl chain on N-dodecyl-DNJ. Analysis of the calculated poses for three different regioisomers indicated an optimal calculated interaction pattern for N,O3-didodecyl-DNJ. The two most promising regioisomers were prepared by a divergent route and their binding to the CERT START domain was evaluated with fluorescence intensity (FLINT) binding assay. N,O3-didodecyl-DNJ was confirmed to be a new binder prototype with level of protein recognition in the FLINT assay comparable to the best known ligands from the alkylated HPA-12 series. This work opens promising perspectives for the development of new inhibitors of CERT-mediated ceramide trafficking.
Identifiants
pubmed: 31757669
pii: S0960-894X(19)30761-9
doi: 10.1016/j.bmcl.2019.126796
pii:
doi:
Substances chimiques
Ceramides
0
Ligands
0
deoxynojirimycine
0
1-Deoxynojirimycin
19130-96-2
CERT1 protein, human
EC 2.7.1.-
Protein Serine-Threonine Kinases
EC 2.7.11.1
Glycoside Hydrolases
EC 3.2.1.-
Glucosamine
N08U5BOQ1K
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
126796Informations de copyright
Copyright © 2019 Elsevier Ltd. All rights reserved.