Rosmarinic Acid as a Potential GSK3β Inhibitor for Autism Spectrum Disorder: Insights from Integrative In-Silico Study

Autism Spectrum Disorder (ASD) is characterized by dysregulated signaling pathways, notably involving Glycogen Synthase Kinase 3 Beta (GSK3β). This in-silico study investigates Rosmarinic acid, a natural polyphenol, as a potential GSK3β inhibitor for ASD. Multiple sequence alignment across six species revealed high conservation of GSK3β’s ATP-binding pocket, underscoring its therapeutic relevance and translatability across model organisms. Molecular docking showed Rosmarinic acid binds robustly to GSK3β’s ATP-binding pocket (estimated affinity: 58.11 nM), surpassing Tideglusib (4077.20 nM) and Laduviglusib (93.26 nM). Rosmarinic acid shares critical binding interactions with Laduviglusib, a previously known and validated GSK3β inhibitor, indicating strong selectivity and efficacy. A 20-nanosecond molecular dynamics (MD) simulation confirmed the stability of the Rosmarinic acid-GSK3β complex with minimal conformational changes. ADMET profiling predicted favorable permeability and low cardiotoxicity, though limited blood-brain barrier penetration suggests advanced delivery strategies for ASD applications. This study positions Rosmarinic acid as a promising natural therapeutic candidate for targeting GSK3β in ASD, with in vitro and in vivo investigations as critical next steps to validate its efficacy.