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Updated: Jul 1, 2026
Fractionation for Resolution of Soluble and Insoluble Huntingtin Species
Published on: February 27, 2018
Rationally Engineered Small Molecules: Pharmacophore Modeling and Molecular Docking Studies Targeting Toxic
Jangampalli Adi Pradeepkiran1, Amardev Rajesh Vatapatri2, Philip Irwin Motakatla3
1Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, TX, 79430, USA.
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, in silico predictions require experimental validation. Future in vitro and in vivo 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.
