Neutral ceramidase-active site inhibitor chemotypes and binding modes.
Colorectal cancer
Neutral ceramidase
Neutral ceramidase inhibitor
nCDase
Journal
Bioorganic chemistry
ISSN: 1090-2120
Titre abrégé: Bioorg Chem
Pays: United States
ID NLM: 1303703
Informations de publication
Date de publication:
10 2023
10 2023
Historique:
received:
21
06
2023
revised:
18
07
2023
accepted:
20
07
2023
medline:
14
8
2023
pubmed:
3
8
2023
entrez:
2
8
2023
Statut:
ppublish
Résumé
Ceramides impact a diverse array of biological functions and have been implicated in disease pathogenesis. The enzyme neutral ceramidase (nCDase) is a zinc-containing hydrolase and mediates the metabolism of ceramide to sphingosine (Sph), both in cells and in the intestinal lumen. nCDase inhibitors based on substrate mimetics, for example C6-urea ceramide, have limited potency, aqueous solubility, and micelle-free fraction. To identify non-ceramide mimetic nCDase inhibitors, hit compounds from an HTS campaign were evaluated in biochemical, cell based and in silico modeling approaches. A majority of small molecule nCDase inhibitors contained pharmacophores capable of zinc interaction but retained specificity for nCDase over zinc-containing acid and alkaline ceramidases, as well as matrix metalloprotease-3 and histone deacetylase-1. nCDase inhibitors were refined by SAR, were shown to be substrate competitive and were active in cellular assays. nCDase inhibitor compounds were modeled by in silico DOCK screening and by molecular simulation. Modeling data supports zinc interaction and a similar compound binding pose with ceramide. nCDase inhibitors were identified with notably improved activity and solubility in comparison with the reference lipid-mimetic C6-urea ceramide.
Identifiants
pubmed: 37531819
pii: S0045-2068(23)00408-X
doi: 10.1016/j.bioorg.2023.106747
pmc: PMC10681040
mid: NIHMS1944191
pii:
doi:
Substances chimiques
Ceramides
0
N-caproylsphingosine
038753E78J
Neutral Ceramidase
EC 3.5.1.23
Sphingosine
NGZ37HRE42
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
106747Subventions
Organisme : NCI NIH HHS
ID : R01 CA221948
Pays : United States
Organisme : NIGMS NIH HHS
ID : R35 GM126906
Pays : United States
Organisme : NIGMS NIH HHS
ID : T32 GM136572
Pays : United States
Organisme : NCI NIH HHS
ID : P01 CA097132
Pays : United States
Organisme : NIGMS NIH HHS
ID : R35 GM128666
Pays : United States
Informations de copyright
Copyright © 2023 Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
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