Discovery of Natural-product Chemotypes with Dual GSK-3ß/HDAC6 Binding Potential via Receptor-guided Pharmacophore Screening, Molecular Docking and Dynamics Simulations

Background: Alzheimer’s disease remains without an effective disease-modifying therapy, largely due to its multifactorial pathology involving tau hyperphosphorylation, amyloid dysregulation, neuroinflammation and neuronal atrophy. Dual inhibition of glycogen synthase kinase-3[Formula: see text] (GSK-3[Formula: see text] and histone deacetylase 6 (HDAC6) — two enzymes central to AD progression — has recently emerged as a promising strategy for simultaneous modulation of these pathogenic pathways. This study aims to identify natural molecules capable of concurrently targeting GSK-3[Formula: see text] and HDAC6 using an integrated computational pipeline. Methods:Receptor-guided pharmacophore models were generated from crystallographic complexes of GSK-3[Formula: see text] and HDAC6 to screen large natural product libraries. Common hits were subjected to molecular docking, MM-GBSA binding free energy estimation, molecular dynamics (MD) simulations and ADMET profiling to assess binding strength, stability and drug-likeness. Results: Eleven phytochemicals satisfied both pharmacophore hypothesis, among which four — Cardamonin, Isorhapontigenin, Neobavaisoflavone (NBI) and Pinostilbene — demonstrated the strongest dual-target complementarity. These compounds achieved docking scores ranging from –7.96 kcal/mol to –9.32 kcal/mol for GSK-3[Formula: see text] and –6.85 kcal/mol to –7.97 kcal/mol for HDAC6. MM-GBSA [Formula: see text] values ranged from –61.04 kcal/mol to –67.37 kcal/mol for GSK-3[Formula: see text] and –31.04 kcal/mol to –38.96 kcal/mol for HDAC6, surpassing co-crystal controls. MD simulations confirmed sustained structural integrity with average RMSD of 1.67–2.01 Å for GSK-3[Formula: see text] and 1.26–2.03 Å for HDAC6. ADMET analysis revealed acceptable CNS permeability, metabolic stability and safety profiles. Conclusion: This study identified four natural-product chemotypes with favorable dual-binding profiles for GSK-3[Formula: see text] and HDAC6. These findings will provide a promising starting point for future biochemical, enzymatic and cellular validation studies, which are essential to confirm their therapeutic potential.