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10.1016-j.dcmed.2022.03.002 |
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|a 2096479X (ISSN)
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|a Molecular docking study of xylogranatins binding to glycogen synthase kinase-3β
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|b KeAi Communications Co.
|c 2022
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|z View Fulltext in Publisher
|u https://doi.org/10.1016/j.dcmed.2022.03.002
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|a Objective: The mangrove tree Xylocarpus granatum J. Koenig (X. granatum) is a medicinal plant used to treat various diseases in several Asian countries. Many bioactive natural products have been isolated from the plants, particularly several groups of limonoids, including 18 xylogranatins (Xyl-A to R), all of which bear a furyl-δ-lactone core commonly found in limonoids. Based on a structural analogy with the limonoids obacunone and gedunin, we hypothesized that xylogranatins could target the enzyme glycogen synthase kinase-3β (GSK-3β), a major target for the treatment of neurodegenerative pathologies, viral infections, and cancers. Methods: We investigated the binding of the 18 xylogranatins to GSK-3β using molecular docking in comparison with two known reference GSK-3β ATP-competitive inhibitors, LY2090314 and AR-A014418. For each compound bound to GSK-3β, the empirical energy of interaction (ΔE) was calculated and compared to that obtained with known GSK-3β inhibitors and limonoid triterpenes that target this enzyme. Results: Five compounds were identified as potential GSK-3β binders, Xyl-A, –C, -J, –N, and –O, for which the calculated empirical ΔE was equivalent to that calculated using the best reference molecule AR-A014418. The best ligand is Xyl-C, which is known to have marked anticancer properties. Binding of Xyl-C to the ATP-binding pocket of GSK-3β positions the furyl-δ-lactone unit deep into the binding-site cavity. Other xylogranatin derivatives bearing a central pyridine ring or a compact polycyclic structure are much less adapted for GSK-3β binding. Structure-binding relationships are discussed. Conclusion: GSK-3β may contribute to the anticancer effects of X. granatum extract. This study paves the way for the identification of other furyl-δ-lactone-containing limonoids as GSK-3β modulators. © 2022 Digital Chinese Medicine
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|a Cancer
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|a Glycogen synthase kinase-3β(GSK-3β)
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|a Limonoids
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|a Molecular modelling
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|a Natural products
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|a Structure-activity relationship
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|a Xylocarpus granatum
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|a Xylogranatins
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|a Bailly, C.
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|a Vergoten, G.
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|t Digital Chinese Medicine
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