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<p>Autism Spectrum Disorder (ASD) is characterized by dysregulated signaling pathways, notably involving Glycogen Synthase Kinase 3 Beta (GSK3β). The present study investigates Rosmarinic acid (RA), a natural polyphenol, as a potential GSK3β inhibitor for ASD using an integrative in silico framework. 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 RA binds robustly to GSK3β’s ATP-binding pocket (estimated affinity: 58.11&#xa0;nM in SeeSAR scoring), compared to previously validated inhibitors such as Tideglusib (4077.20&#xa0;nM in SeeSAR scoring) and Laduviglusib (93.26&#xa0;nM in SeeSAR scoring). Independent Glide docking reproduced the binding orientation (GlideScore: − 7.548&#xa0;kcal/mol), and MM-GBSA refinement indicated favorable binding free energy (ΔG<sub>bind</sub> = − 42.37&#xa0;kcal/mol). A 100&#xa0;ns molecular dynamics simulation demonstrated stable ligand retention and sustained catalytic pocket interactions with the engagement of catalytic amino acid residues including Lys85 and Asp200. Off-target docking against CDK2, CDK5, and GSK3α suggested preferential binding toward GSK3β. Structure-activity exploration of RA analogs identified aromatic balance and moderated polarity as determinants of predicted affinity. Together, these findings provide convergent computational evidence that RA may directly interact with GSK3β, supporting further biochemical and cellular validation studies to assess its potential as a modulator of GSK3β-associated pathways relevant to ASD pathophysiology.</p>

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Rosmarinic acid as a potential GSK3β inhibitor for autism spectrum disorder: insights from an integrative in silico study

  • 期刊论文

  • 发表日期：

    2026年4月28日

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  • Priya Joon,
  • Saumya Bansal,
  • Jesil Mathew Aranjani,
  • Anil Kumar,
  • Deepak Deepak

摘要

Autism Spectrum Disorder (ASD) is characterized by dysregulated signaling pathways, notably involving Glycogen Synthase Kinase 3 Beta (GSK3β). The present study investigates Rosmarinic acid (RA), a natural polyphenol, as a potential GSK3β inhibitor for ASD using an integrative in silico framework. 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 RA binds robustly to GSK3β’s ATP-binding pocket (estimated affinity: 58.11 nM in SeeSAR scoring), compared to previously validated inhibitors such as Tideglusib (4077.20 nM in SeeSAR scoring) and Laduviglusib (93.26 nM in SeeSAR scoring). Independent Glide docking reproduced the binding orientation (GlideScore: − 7.548 kcal/mol), and MM-GBSA refinement indicated favorable binding free energy (ΔGbind = − 42.37 kcal/mol). A 100 ns molecular dynamics simulation demonstrated stable ligand retention and sustained catalytic pocket interactions with the engagement of catalytic amino acid residues including Lys85 and Asp200. Off-target docking against CDK2, CDK5, and GSK3α suggested preferential binding toward GSK3β. Structure-activity exploration of RA analogs identified aromatic balance and moderated polarity as determinants of predicted affinity. Together, these findings provide convergent computational evidence that RA may directly interact with GSK3β, supporting further biochemical and cellular validation studies to assess its potential as a modulator of GSK3β-associated pathways relevant to ASD pathophysiology.