DISCOVERY OF POTENTIAL GSK-3β INHIBITORS AGAINST ALZHEIMER’S DISEASE: IN SILICO DESIGN AND PHARMACOKINETIC EVALUATION OF N-(ANTHRACENE-1-YL)-2-PHENOXYACETAMIDE ANALOGS
DOI:
https://doi.org/10.22159/ijap.2026v18i4.58331Keywords:
Alzheimer’s disease, GSK-3β inhibitors, Molecular docking, MM-GBSA, ADMET profiling, In silico drug designAbstract
Objectives: Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterised by memory loss and cognitive decline. Glycogen Synthase Kinase-3β (GSK-3β) regulates tau phosphorylation, making it a promising therapeutic target. To the best of our knowledge, N-(anthracene-1-yl)-2-phenoxyacetamide analogues have not been reported as GSK-3β inhibitors. This study aimed to design and evaluate a novel series of these analogues as potential GSK-3β inhibitors using computational approaches.
Methods: Ten ligands were designed and docked using Glide XP against GSK-3β (PDB ID: 1J1C). Binding stability was assessed through molecular mechanics-generalised born surface area (MM-GBSA) free energy calculations. Absorption, distribution, metabolism and excretion (ADMET) profiling (drug-likeness, toxicity) and protein-ligand interaction analysis were also performed.
Results: Compounds 2(N-(anthracen-1-yl)-2-(4-hydroxyphenoxy)acetamide) and compound 3(2-(4-aminophenoxy)-N-(anthracen-1-yl)acetamide) showed docking scores (-5.45 and -5.79 kcal/mol) comparable to or better than the co-crystallised ligand (-5.40 kcal/mol). Since no approved drug directly targets GSK-3β, Donepezil (an FDA-approved acetylcholinesterase inhibitor for AD) was included as a reference comparator, against which both compounds performed better (-3.63 kcal/mol). MM-GBSA confirmed favorable binding free energies (-65.81 and -67.21 kcal/mol). ADMET predictions indicated Lipinski compliance, good oral absorption, CNS penetration and low toxicity. Interaction analysis revealed stable hydrogen bonding with Lys85 and Asn186, two critical residues of the GSK-3β catalytic site.
Conclusion: Based on this computational analysis, compounds 2 and 3 demonstrated favourable pharmacokinetic features, significant binding affinity and binding stability. These scaffolds are therefore seen to be potential as GSK-3β targeting anti-Alzheimer's drugs. These chemicals require more in vitro and in vivo research.
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Copyright (c) 2026 AKSHAYA MA, AKSHYA AM, BAVANSUDHAN PS, DHANUSHYA P., RAKSHITHA ANANDAGIRI, ASTAJOTHI R., MUTHUKUMARAN M., KOPPULA JAYANTHI
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