Gliflozins, sucrose and flavonoids are allosteric activators of lecithin-cholesterol acyltransferase.
Journal
Scientific reports
ISSN: 2045-2322
Titre abrégé: Sci Rep
Pays: England
ID NLM: 101563288
Informations de publication
Date de publication:
30 10 2024
30 10 2024
Historique:
received:
24
07
2024
accepted:
18
10
2024
medline:
31
10
2024
pubmed:
31
10
2024
entrez:
31
10
2024
Statut:
epublish
Résumé
Lecithin-cholesterol acyltransferase (LCAT) serves as a pivotal enzyme in preserving cholesterol homeostasis via reverse cholesterol transport, a process closely associated with the onset of atherosclerosis. Impaired LCAT function can lead to severe LCAT deficiency disorders for which no pharmacological treatment exists. LCAT-based therapies, such as small molecule positive allosteric modulators (PAMs), against LCAT deficiencies and atherosclerosis hold promise, although their efficacy against atherosclerosis remains challenging. Herein we utilized a quantitative in silico metric to predict the activity of novel PAMs and tested their potencies with in vitro enzymatic assays. As predicted, sodium-glucose cotransporter 2 (SGLT2) inhibitors (gliflozins), sucrose and flavonoids activate LCAT. This has intriguing implications for the mechanism of action of gliflozins, which are commonly used in the treatment of type 2 diabetes, and for the endogenous activation of LCAT. Our results underscore the potential of molecular dynamics simulations in rational drug design.
Identifiants
pubmed: 39478139
doi: 10.1038/s41598-024-77104-3
pii: 10.1038/s41598-024-77104-3
doi:
Substances chimiques
Phosphatidylcholine-Sterol O-Acyltransferase
EC 2.3.1.43
Flavonoids
0
Sucrose
57-50-1
Sodium-Glucose Transporter 2 Inhibitors
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
26085Subventions
Organisme : Research Council of Finland
ID : 350636
Informations de copyright
© 2024. The Author(s).
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