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Binding mechanism and biological effects of flavone DYRK1A inhibitors for the design of new antidiabetics.
Sci. Rep. 13:18114 (2023)
The selective inhibition of kinases from the diabetic kinome is known to promote the regeneration of beta cells and provide an opportunity for the curative treatment of diabetes. The effect can be achieved by carefully tailoring the selectivity of inhibitor toward a particular kinase, especially DYRK1A, previously associated with Down syndrome and Alzheimer's disease. Recently DYRK1A inhibition has been shown to promote both insulin secretion and beta cells proliferation. Here, we show that commonly available flavones are effective inhibitors of DYRK1A. The observed biochemical activity of flavone compounds is confirmed by crystal structures solved at 2.06 Å and 2.32 Å resolution, deciphering the way inhibitors bind in the ATP-binding pocket of the kinase, which is driven by the arrangement of hydroxyl moieties. We also demonstrate antidiabetic properties of these biomolecules and prove that they could be further improved by therapy combined with TGF-β inhibitors. Our data will allow future structure-based optimization of the presented scaffolds toward potent, bioavailable and selective anti-diabetic drugs.
Impact Factor
Scopus SNIP
Altmetric
4.600
0.000
Anmerkungen
Besondere Publikation
Auf Hompepage verbergern
Publikationstyp
Artikel: Journalartikel
Dokumenttyp
Wissenschaftlicher Artikel
Schlagwörter
Beta-cell Proliferation; Alzheimers-disease; Rutin Improves; Molecular Docking; Oxidative Stress; Protein-kinase; Quercetin; Gossypin; Model; Activation
Sprache
englisch
Veröffentlichungsjahr
2023
HGF-Berichtsjahr
2023
ISSN (print) / ISBN
2045-2322
e-ISSN
2045-2322
Zeitschrift
Scientific Reports
Quellenangaben
Band: 13,
Heft: 1,
Artikelnummer: 18114
Verlag
Nature Publishing Group
Verlagsort
London
Begutachtungsstatus
Peer reviewed
Institut(e)
Institute of Structural Biology (STB)
POF Topic(s)
30203 - Molecular Targets and Therapies
Forschungsfeld(er)
Enabling and Novel Technologies
PSP-Element(e)
G-503000-001
Förderungen
Priority Research Area BioS under the program 'Initiative of Excellence-Research University' at the Jagiellonian University in Krakow
DESY (Hamburg, Germany)
(Foundation for Polish Science)
TEAM
National Science Centre
This work was supported by a grant from the National Science Centre (UMO-2019/34/E/NZ1/00467) and by NAWA Polish Returns 2018 (PPN/PPO/2018/1/00046/U/00001) to A.C. We acknowledge the MCB Structural Biology Core Facility (supported by the TEAM TECH CORE F
DESY (Hamburg, Germany)
(Foundation for Polish Science)
TEAM
National Science Centre
This work was supported by a grant from the National Science Centre (UMO-2019/34/E/NZ1/00467) and by NAWA Polish Returns 2018 (PPN/PPO/2018/1/00046/U/00001) to A.C. We acknowledge the MCB Structural Biology Core Facility (supported by the TEAM TECH CORE F
WOS ID
001087271600059
Scopus ID
85174731406
PubMed ID
37872245
Erfassungsdatum
2023-11-28