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<p>Glycogen synthase kinase-3β (GSK-3β) is a key therapeutic target for Alzheimer’s disease, but identifying safe, brain-penetrant inhibitors remains difficult. This study aimed to discover novel CNS-active GSK-3β inhibitors using a rigorous multi-tier computational pipeline. The workflow combined ligand-based and structure-based pharmacophore modeling, virtual screening of the ZINCPharmer database, AutoDock Vina docking, ADME and blood-brain barrier (BBB) filtering with SwissADME, toxicity prediction using ProTox-3.0, and validation by 100-ns molecular dynamics simulations with MM/GBSA and MM/PBSA free energy calculations. Pharmacophore screening with a ≤ 1.0 Å RMSD cutoff identified 1,085 ligand-based and 36 structure-based hits. After docking and developability filtering, two BBB-permeant candidates were prioritized: <b>SB1</b>, a structure-based hit (predicted LD<sub>50</sub> = 2500&#xa0;mg/kg, toxicity class 5), and <b>LB1</b>, a ligand-based hit (predicted LD<sub>50</sub> = 521&#xa0;mg/kg, toxicity class 4). Molecular dynamics confirmed stable binding for both compounds. MM/GBSA analysis showed favorable binding free energies for <b>SB1</b> (-27.68&#xa0;kcal/mol) and <b>LB1</b> (-25.74&#xa0;kcal/mol), both surpassing the co-crystallized reference (-8.75&#xa0;kcal/mol). These findings identify <b>SB1</b> and <b>LB1</b> as promising, safe, and brain-penetrant GSK-3β lead compounds for experimental validation in Alzheimer’s disease.</p>

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In silico pipeline for GSK 3β inhibitor discovery in Alzheimer’s disease using pharmacophore screening, docking, ADME filtering, and MD validation

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年7月23日

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  • Mahmoud S. Elkotamy,
  • Mohamed K. Elgohary,
  • Ahmed S. Alkotami,
  • Mohamed M. Eldesouki,
  • Zainab M. Elsayed,
  • Amr A. Mattar,
  • Mahmoud F. Abo-Ashour,
  • Haytham O. Tawfik,
  • Wagdy M. Eldehna,
  • Hatem A. Abdel-Aziz

摘要

Glycogen synthase kinase-3β (GSK-3β) is a key therapeutic target for Alzheimer’s disease, but identifying safe, brain-penetrant inhibitors remains difficult. This study aimed to discover novel CNS-active GSK-3β inhibitors using a rigorous multi-tier computational pipeline. The workflow combined ligand-based and structure-based pharmacophore modeling, virtual screening of the ZINCPharmer database, AutoDock Vina docking, ADME and blood-brain barrier (BBB) filtering with SwissADME, toxicity prediction using ProTox-3.0, and validation by 100-ns molecular dynamics simulations with MM/GBSA and MM/PBSA free energy calculations. Pharmacophore screening with a ≤ 1.0 Å RMSD cutoff identified 1,085 ligand-based and 36 structure-based hits. After docking and developability filtering, two BBB-permeant candidates were prioritized: SB1, a structure-based hit (predicted LD50 = 2500 mg/kg, toxicity class 5), and LB1, a ligand-based hit (predicted LD50 = 521 mg/kg, toxicity class 4). Molecular dynamics confirmed stable binding for both compounds. MM/GBSA analysis showed favorable binding free energies for SB1 (-27.68 kcal/mol) and LB1 (-25.74 kcal/mol), both surpassing the co-crystallized reference (-8.75 kcal/mol). These findings identify SB1 and LB1 as promising, safe, and brain-penetrant GSK-3β lead compounds for experimental validation in Alzheimer’s disease.