Known Drugs Identified by Structure-Based Virtual Screening Are Able to Bind Sigma-1 Receptor and Increase Growth of Huntington Disease Patient-Derived Cells.
Known Drugs Identified by Structure-Based Virtual Screening Are Able to Bind Sigma-1 Receptor and Increase Growth of Huntington Disease Patient-Derived Cells.
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DOI：
10.3390/ijms22031293
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发表时间：
2021-01-28
影响因子：
5.6
通讯作者：
Ilari A
中科院分区：
文献类型：
--
作者：
Battista T;Pascarella G;Staid DS;Colotti G;Rosati J;Fiorillo A;Casamassa A;Vescovi AL;Giabbai B;Semrau MS;Fanelli S;Storici P;Squitieri F;Morea V;Ilari A
亨廷顿病（HD）是一种破坏性的且目前无法治疗的神经退行性疾病，其特征在于进行性的运动和精神表现的致残。σ-1受体（σ 1R）是在中枢神经系统中表达的蛋白质，其3D结构最近已通过X射线晶体学确定，并且其激动剂已显示在神经退行性疾病中具有神经保护活性。（i）通过虚拟筛选预测通过ZINC数据库公开可获得的FDA批准的药物与σ 1R相互作用的能力，随后对20种得分最高的药物进行计算对接和视觉检查;和（ii）评估通过计算分析选择的六种药物在体外通过表面等离子体共振直接结合纯化的σ 1R并改善从HD患者获得的成纤维细胞生长的能力，其相对于对照细胞显著受损。所有六种选定的药物都证明能够在体外直接结合纯化的σ 1R，并改善来自两个或一个HD患者的HD细胞的生长。这些结果支持本文实施的药物重新定位程序用于识别针对HD的新治疗工具的有效性。
Huntington disease (HD) is a devastating and presently untreatable neurodegenerative disease characterized by progressively disabling motor and mental manifestations. The sigma-1 receptor (σ1R) 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 σ1R 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 σ1R 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 σ1R 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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影响因子：
8.8
作者：
Hosp, Fabian;Vossfeldt, Hannes;Heinig, Matthias;Vasiljevic, Djordje;Arumughan, Anup;Wyler, Emanuel;Landthaler, Markus;Hubner, Norbert;Wanker, Erich E.;Lannfelt, Lars;Ingelsson, Martin;Lalowski, Maciej;Voigt, Aaron;Selbach, Matthias
通讯作者：
Selbach, Matthias
DOI：
10.1212/nxg.0000000000000275
发表时间：
2018-10
期刊：
Neurology. Genetics
影响因子：
--
作者：
Gardiner SL;Milanese C;Boogaard MW;Buijsen RAM;Hogenboom M;Roos RAC;Mastroberardino PG;van Roon-Mom WMC;Aziz NA
通讯作者：
Aziz NA
影响因子：
2.9
作者：
Gund, TM;Floyd, J;Jung, D
通讯作者：
Jung, D
影响因子：
4.8
作者：
Hong, Weimin Conrad;Yano, Hideaki;Katz, Jonathan L.
通讯作者：
Katz, Jonathan L.
影响因子：
9
作者：
Genovese I;Giamogante F;Barazzuol L;Battista T;Fiorillo A;Vicario M;D'Alessandro G;Cipriani R;Limatola C;Rossi D;Sorrentino V;Poser E;Mosca L;Squitieri F;Perluigi M;Arena A;van Petegem F;Tito C;Fazi F;Giorgi C;Calì T;Ilari A;Colotti G
通讯作者：
Colotti G