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Mediterranean Journal of Medical Research
https://mrj.org.ly/article/doi/10.5281/zenodo.18945545

Mediterranean Journal of Medical Research

Original article Medicinal chemistry

Computational screening of natural small molecules as dual ATXN3 and LC3 binders for an autophagy-based strategy in spinocerebellar ataxia type 3

Shada H. Alharati, Halima A. Gbaj, Mohamed A. Gbaj, Anton Hermann, Abdul M. Gbaj

http://dx.doi.org/10.5281/zenodo.18945545 Mediterr J Med Res, vol.3, n1, p.94-104, 2026
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Abstract

Spinocerebellar ataxia type 3 (SCA3) is an autosomal dominant neurodegenerative disorder caused by a CAG repeat expansion in the ATXN3 gene, producing a polyglutamine expanded ataxin‑3 protein that misfolds, aggregates, and drives progressive neurodegeneration. Enhancing the selective autophagic clearance of mutant ATXN3 through recruitment to the autophagy adaptor LC3 on autophagosomal membranes represents a promising disease-modifying strategy. This study investigates whether natural small molecules can act as dual binders of ATXN3 and LC3, providing accessible scaffolds for an autophagy-based therapeutic approach in SCA3. The Josephin domain of human ATXN3 and human LC3 were prepared as receptor structures. Five natural ligands, quercetin, kaempferol, luteolin, rutin, and trehalose, were subjected to Vina-based molecular docking. For each ligand-target pair, the lowest energy pose was selected and analyzed for predicted binding free energies (ΔG, kcal/mol), hydrogen bond networks, and hydrophobic contacts. Pharmacokinetic properties were evaluated using SwissADME to assess drug likeness and oral bioavailability. Quercetin, kaempferol, and luteolin showed strong and balanced predicted binding to ATXN3 (-8.5 to -8.1 kcal/mol) and LC3 (-8.4 to -8.3 kcal/mol), with molecular weights 286-302 g/mol, high predicted gastrointestinal absorption, and no Lipinski violations. Rutin and trehalose bound ATXN3 weakly (-6.4 and -5.2 kcal/mol, respectively) but displayed strong ending to LC3 (-10.3 and -7.8 kcal/mol), though with poor oral drug-like properties (MW 610.52 and 342.30 g/mol, respectively, low gastrointestinal absorption and multiple Lipinski violations. Common natural flavonoids, particularly quercetin, kaempferol, and luteolin, exhibit strong dual-target binding with favorable oral drug-like properties, supporting their potential as simple scaffolds for autophagy-based therapeutic strategies in SCA3. These findings provide a clear rationale for subsequent biochemical and cellular validation of their ATTEC like mechanisms.

Keywords

AutoDock vina, autophagosome docking, dual target binding, SwissADME, pharmacokinetics

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Submitted date:
11/09/2025

Reviewed date:
02/25/2026

Accepted date:
03/03/2026

Publication date:
03/10/2026

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