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image of Rationally Engineered Small Molecules: Pharmacophore Modeling and Molecular  Docking  Studies   Targeting   Toxic  Polyglutamine  (PolyQ) Repeats in Huntington’s Disease

Abstract

Introduction

Huntington’s disease (HD) is a progressive neurodegenerative disorder caused by the accumulation of mutant huntingtin protein (mHTT) with expanded polyglutamine (polyQ) tracts. These aggregates contribute to neuronal toxicity and disease progression. Targeting aggregation, especially at the N-terminal domain (N17), may offer a therapeutic strategy. This study aims to identify potential small-molecule inhibitors that can bind to aggregation-prone regions of mHTT using computational methods.

Methods

We characterized polyQ repeat regions and the N17 domain using CASTp to identify active sites. Pharmacophore models were generated using LigandScout based on the glutamate inhibitor 6-Diazo-5-oxo-L-norleucine (DON). Structurally similar ligands were screened from PubChem. Ten candidates were selected and evaluated through molecular docking. ADME/Toxicity and drug-likeness analyses were performed to assess pharmacokinetic suitability.

Results

Ten DON-like ligands showed favorable pharmacophore features. Docking studies identified five compounds with strong binding affinities and key interactions with the polyQ region. These top candidates also demonstrated acceptable ADMET profiles and drug-likeness.

Discussion

The five lead compounds identified in this study demonstrate potential to interfere with mHTT aggregation, a key pathological feature of HD. Their favorable binding and pharmacokinetic properties support their candidacy for further development. However, predictions require experimental validation. Future and studies are essential to confirm their efficacy and safety.

Conclusion

This study presents five promising small-molecule inhibitors for HD, laying the groundwork for future therapeutic development targeting mHTT aggregation.

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2025-10-21
2025-12-15

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Rationally Engineered Small Molecules: Pharmacophore Modeling and Molecular  Docking  Studies   Targeting   Toxic  Polyglutamine  (PolyQ) Repeats in Huntington’s Disease
Bentham Science Publishers ; https://doi.org/10.2174/0113894501393938251006195954
/content/journals/cdt/10.2174/0113894501393938251006195954
/content/journals/cdt/10.2174/0113894501393938251006195954
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  • Article Type:     Research Article
Keywords: Huntington's disease ; polyglutamine ; molecular docking studies ; pharmacophore ; ligands ; mutant huntingtin

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