Computational analysis of zoanthamine alkaloids from Zoanthus sp. as potential DKK1 and GSK-3β inhibitors for osteoporosis therapy via Wnt signaling.

Marine invertebrates are a rich source of structurally diverse secondary metabolites with broad biological activities, making them valuable for drug discovery. The genus Zoanthus is particularly noteworthy, producing numerous bioactive alkaloids, including the zoanthamines, which show promise in treating osteoporosis. Osteoporosis, a debilitating bone disease characterized by reduced bone mineral density and increased fracture risk, is linked to Wnt signaling pathway dysregulation. This highly conserved pathway maintains tissue homeostasis and is crucial for neurogenesis, synapse formation, and bone development. Dickkopf-1 (DKK1) and glycogen synthase kinase-3β (GSK-3β), key Wnt pathway regulators, are established therapeutic targets for osteoporosis. This study employed an integrated computational approach-combining molecular docking, extensive molecular dynamics (MD) simulations, and density functional theory (DFT) calculations-to assess the inhibitory potential of 69 zoanthamine-type alkaloids against DKK1 and GSK-3β. MD simulations, analyzing root mean square deviation (RMSD), root mean square fluctuation (RMSF), radius of gyration, and free energy landscape, provided insights into protein-ligand complex stability and key interactions. Binding free energies were calculated using the MM-PBSA method combined with interaction entropy. DFT calculations further elucidated the electronic structure and reactivity of the most promising inhibitors (3α-hydroxyzoanthenamine, epioxyzoanthamine, 7α-hydroxykuroshine E, and norzoanthamine), which exhibited favorable binding interactions with key residues in target proteins. This integrative approach demonstrates the power of computational methods in drug discovery, highlighting the potential of zoanthamine alkaloids as lead compounds for innovative osteoporosis therapies.