期刊
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
卷 22, 期 3, 页码 -出版社
MDPI
DOI: 10.3390/ijms22031293
关键词
Huntington disease (HD); sigma-1 receptor (σ 1R); drug repositioning; virtual screening; computational docking; structure analysis; surface plasmon resonance (SPR); cellular models
资金
- Ministero della Salute [Ricerca Corrente 2019-2020, RF-2016-02364123] Funding Source: Medline
- Ministero dell'Istruzione, dell'Università e della Ricerca [2017483NH8_005] Funding Source: Medline
The study utilized a drug repositioning strategy to identify six drugs that can directly bind sigma 1R and improve the growth of cells from Huntington disease patients. These drugs have shown efficacy in providing new therapeutic tools against HD, offering hope for future treatments.
Huntington disease (HD) is a devastating and presently untreatable neurodegenerative disease characterized by progressively disabling motor and mental manifestations. The sigma-1 receptor (sigma 1R) is a protein expressed in the central nervous system, whose 3D structure has been recently determined by X-ray crystallography and whose agonists have been shown to have neuroprotective activity in neurodegenerative diseases. To identify therapeutic agents against HD, we have implemented a drug repositioning strategy consisting of: (i) Prediction of the ability of the FDA-approved drugs publicly available through the ZINC database to interact with sigma 1R by virtual screening, followed by computational docking and visual examination of the 20 highest scoring drugs; and (ii) Assessment of the ability of the six drugs selected by computational analyses to directly bind purified sigma 1R in vitro by Surface Plasmon Resonance and improve the growth of fibroblasts obtained from HD patients, which is significantly impaired with respect to control cells. All six of the selected drugs proved able to directly bind purified sigma 1R in vitro and improve the growth of HD cells from both or one HD patient. These results support the validity of the drug repositioning procedure implemented herein for the identification of new therapeutic tools against HD.
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