Discovery of new erbB4 inhibitors: Repositioning an orphan chemical library by inverse virtual screening

Eur J Med Chem. 2018 May 25:152:253-263. doi: 10.1016/j.ejmech.2018.04.018. Epub 2018 Apr 12.

Abstract

Inverse Virtual Screening (IVS) is a docking based approach aimed to the evaluation of the virtual ability of a single compound to interact with a library of proteins. For the first time, we applied this methodology to a library of synthetic compounds, which proved to be inactive towards the target they were initially designed for. Trifluoromethyl-benzenesulfonamides 3-21 were repositioned by means of IVS identifying new lead compounds (14-16, 19 and 20) for the inhibition of erbB4 in the low micromolar range. Among these, compound 20 exhibited an interesting value of IC50 on MCF7 cell lines, thus validating IVS in lead repurposing.

Keywords: Antitumor compounds; Dual inhibitors; Inverse virtual screening; Lead repurposing; erbB4 inhibitors.

MeSH terms

  • Benzenesulfonamides
  • Cell Cycle Checkpoints / drug effects
  • Dose-Response Relationship, Drug
  • Drug Discovery*
  • Humans
  • MCF-7 Cells
  • Molecular Docking Simulation*
  • Molecular Structure
  • Receptor, ErbB-4 / antagonists & inhibitors*
  • Receptor, ErbB-4 / metabolism
  • Small Molecule Libraries / chemical synthesis
  • Small Molecule Libraries / chemistry
  • Small Molecule Libraries / pharmacology*
  • Structure-Activity Relationship
  • Sulfonamides / chemical synthesis
  • Sulfonamides / chemistry
  • Sulfonamides / pharmacology*
  • Tumor Cells, Cultured

Substances

  • Small Molecule Libraries
  • Sulfonamides
  • ERBB4 protein, human
  • Receptor, ErbB-4