Christian Bailly 1Gérard Vergoten2
作者信息
- 1. Scientific Consulting Office, OncoWitan, Wasquehal, Lille 59290, France
- 2. University of Lille, Inserm, INFINITE - U1286, Institut de Chimie Pharmaceutique Albert Lespagnol (ICPAL), Faculty of Pharmacy, 3 rue du Professeur Laguesse, BP-83, F-59006, Lille, France
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摘要
Abstract
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, includ-ing 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 hy-pothesized that xylogranatins could target the enzyme glycogen synthase kinase-3β (GSK-3β), a major target for the treatment of neurodegenerative pathologies, viral infections, and can-cers.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 inhibit-ors 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 ref-erence molecule AR-A014418. The best ligand is Xyl-C, which is known to have marked antic-ancer 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 cent-ral 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.关键词
天然产物/木果楝/木果楝亭/糖原合成酶激酶-3β/柠檬苦素类似物/癌症/分子建模/构效关系Key words
Natural products/Xylocarpus granatum/Xylogranatins/Glycogen synthase kinase-3β (GSK-3β)/Limonoids/Cancer/Molecular modelling/Structure-activity relationship
