Natural compound screening predicts novel GSK-3 isoform-specific inhibitors.

Autor: Ahmad F; Department of Basic Medical Sciences, College of Medicine, University of Sharjah, Sharjah, 27272, United Arab Emirates; Cardiovascular Research Group, Research Institute for Medical and Health Sciences, University of Sharjah, Sharjah, 27272, United Arab Emirates; Space Medicine Research Group, Research Institute for Medical and Health Sciences, University of Sharjah, Sharjah, 27272, United Arab Emirates. Electronic address: fahmad@sharjah.ac.ae., Gupta A; Cardiovascular Research Group, Research Institute for Medical and Health Sciences, University of Sharjah, Sharjah, 27272, United Arab Emirates., Marzook H; Cardiovascular Research Group, Research Institute for Medical and Health Sciences, University of Sharjah, Sharjah, 27272, United Arab Emirates., Woodgett JR; Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, ON, Canada., Saleh MA; Cardiovascular Research Group, Research Institute for Medical and Health Sciences, University of Sharjah, Sharjah, 27272, United Arab Emirates; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, 35516, Egypt; Department of Clinical Sciences, College of Medicine, University of Sharjah, Sharjah, 27272, United Arab Emirates., Qaisar R; Department of Basic Medical Sciences, College of Medicine, University of Sharjah, Sharjah, 27272, United Arab Emirates; Cardiovascular Research Group, Research Institute for Medical and Health Sciences, University of Sharjah, Sharjah, 27272, United Arab Emirates; Space Medicine Research Group, Research Institute for Medical and Health Sciences, University of Sharjah, Sharjah, 27272, United Arab Emirates.
Jazyk: angličtina
Zdroj: Biochimie [Biochimie] 2024 Oct; Vol. 225, pp. 68-80. Date of Electronic Publication: 2024 May 07.
DOI: 10.1016/j.biochi.2024.05.002
Abstrakt: Glycogen synthase kinase-3 (GSK-3) plays important roles in the pathogenesis of cardiovascular, metabolic, neurological disorders and cancer. Isoform-specific loss of either GSK-3α or GSK-3β often provides cytoprotective effects under such clinical conditions. However, available synthetic small molecule inhibitors are relatively non-specific, and their chronic use may lead to adverse effects. Therefore, screening for natural compound inhibitors to identify the isoform-specific inhibitors may provide improved clinical utility. Here, we screened 70 natural compounds to identify novel natural GSK-3 inhibitors employing comprehensive in silico and biochemical approaches. Molecular docking and pharmacokinetics analysis identified two natural compounds Psoralidin and Rosmarinic acid as potential GSK-3 inhibitors. Specifically, Psoralidin and Rosmarinic acid exhibited the highest binding affinities for GSK-3α and GSK-3β, respectively. Consistent with in silico findings, the kinase assay-driven IC50 revealed superior inhibitory effects of Psoralidin against GSK-3α (IC50 = 2.26 μM) vs. GSK-3β (IC50 = 4.23 μM) while Rosmarinic acid was found to be more potent against GSK-3β (IC50 = 2.24 μM) than GSK-3α (IC50 = 5.14 μM). Taken together, these studies show that the identified natural compounds may serve as GSK-3 inhibitors with Psoralidin serving as a better inhibitor for GSK-3α and Rosmarinic for GSK-3β isoform, respectively. Further characterization employing in vitro and preclinical models will be required to test the utility of these compounds as GSK-3 inhibitors for cardiometabolic and neurological disorders and cancers.
Competing Interests: Declaration of competing interest The authors declared no competing interest concerning the research, authorship, and/or publication of this article.
(Copyright © 2024 Elsevier B.V. and Société Française de Biochimie et Biologie Moléculaire (SFBBM). All rights reserved.)
Databáze: MEDLINE
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