In silico identification and in vivo characterization of small molecule therapeutic hypothermia mimetics

Bioorg Med Chem. 2017 Dec 15;25(24):6597-6604. doi: 10.1016/j.bmc.2017.10.039. Epub 2017 Oct 31.

Abstract

Hypothermia has been proved to have a beneficial effect on several pathologies. CIRBP is one of the so termed cold-shock proteins involved in this process. In this work, we have detected small molecules capable of modulating the activity of CIRBP in the absence of a cold stimulus, by High Throughput Virtual Screening (HTVS) of the Diversity Set IV of the NCI and 15 compounds of our in-house data base. Fifteen compounds were selected from the HTVS to carry out a second screening through a cell-based Western blot assay. This assay, together with molecular modeling studies allowed us to select compound zr17-2 for an in vivo experiment, which showed an interesting increase of CIRBP expression in several organs of experimental animals. Therefore, we have demonstrated that the effect of hypothermia can be mimicked by small molecules, which can be developed as first-in-class new drugs for the treatment of several diseases.

Keywords: CIRBP; Cold-shock protein; HTVS; Hypothermia mimetics; Molecular modeling.

MeSH terms

  • Animals
  • Cell Line
  • Cold Shock Proteins and Peptides / biosynthesis
  • Dose-Response Relationship, Drug
  • High-Throughput Screening Assays
  • Hypothermia / drug therapy*
  • Hypothermia / metabolism
  • Male
  • Models, Molecular
  • Molecular Structure
  • RNA-Binding Proteins / biosynthesis
  • Rats
  • Small Molecule Libraries / chemical synthesis
  • Small Molecule Libraries / chemistry
  • Small Molecule Libraries / therapeutic use*
  • Structure-Activity Relationship

Substances

  • Cirbp protein, rat
  • Cold Shock Proteins and Peptides
  • RNA-Binding Proteins
  • Small Molecule Libraries