Known drugs identified by structure-based virtual screening are able to bind sigma-1 receptor and increase growth of huntington disease patient-derived cells

Theo Battista, Gianmarco Pascarella, David Sasah Staid, Gianni Colotti, Jessica Rosati, Annarita Fiorillo, Alessia Casamassa, Angelo Luigi Vescovi, Barbara Giabbai, Marta Stefania Semrau, Sergio Fanelli, Paola Storici, Ferdinando Squitieri, Veronica Morea, Andrea Ilari

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

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 neuro-protective 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 fibro-blasts 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.

Original languageEnglish (US)
Article number1293
Pages (from-to)1-26
Number of pages26
JournalInternational journal of molecular sciences
Volume22
Issue number3
DOIs
StatePublished - Feb 1 2021

Keywords

  • Cellular models
  • Computational docking
  • Drug repositioning
  • Huntington disease (HD)
  • Sigma-1 receptor (σ1R)
  • Structure analysis
  • Surface plasmon resonance (SPR)
  • Virtual screening

ASJC Scopus subject areas

  • Catalysis
  • Molecular Biology
  • Spectroscopy
  • Computer Science Applications
  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Inorganic Chemistry

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