Molecular docking study of GSK-3β interaction with nomilin, kihadanin B, and related limonoids and triterpenes with a furyl-δ-lactone core.

Glycogen synthase kinase-3β (GSK-3β) is a target enzyme considered for the treatment of multiple human diseases, from neurodegenerative pathologies to viral infections and cancers. Numerous inhibitors of GSK-3β have been discovered but thus far only a few have reached clinical trials and only one drug, tideglusib (1), has been registered. Natural products targeting GSK-3β have been identified, including the two anticancer limonoids obacunone (5) and gedunin (4), both presenting a furyl-δ-lactone core. To help identifying novel GSK-3β ligands, we have performed a molecular docking study with 15 complementary natural products bearing a furyl-δ-lactone unit (such as limonin (6) and kihadanins A (8) and B (9)) or a closely related structure (such as cedrelone (10) and nimbolide (11)). The formation of GSK-3β-binding complexes for those natural products was compared to reference GSK-3β ATP-competitive inhibitors LY2090314 (3) and AR-A014418 (2). Our in silico analysis led to the identification of two new GSK-3β-binding natural products: kihadanin B (9) and nomilin (7). The latter surpassed the reference compounds in terms of calculated empirical energy of interaction (ΔE). Nomilin (7) can possibly bind to the active site of GSK-3β, notably via the furyl-δ-lactone core and its 1-acetyl group, implicated in the protein interaction. Compound structure-binding relationships are discussed. The study should help the discovery of novel natural products targeting GSK-3β.