Molecular docking study of xylogranatins binding to glycogen synthase kinase-3β
- Author:
Christian Bailly
1
;
Gérard Vergoten
2
Author Information
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
- Publication Type:Journal Article
- From:
Digital Chinese Medicine
2022;5(1):9-17
- CountryChina
- Language:English
-
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, 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.
- Full text:Bailly.docx
