LAUSR

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.