Discovery of Immunoproteasome Inhibitors Using Large-Scale Covalent Virtual Screening

Molecules. 2019 Jul 16;24(14):2590. doi: 10.3390/molecules24142590.

Abstract

Large-scale virtual screening of boronic acid derivatives was performed to identify nonpeptidic covalent inhibitors of the β5i subunit of the immunoproteasome. A hierarchical virtual screening cascade including noncovalent and covalent docking steps was applied to a virtual library of over 104,000 compounds. Then, 32 virtual hits were selected, out of which five were experimentally confirmed. Biophysical and biochemical tests showed micromolar binding affinity and time-dependent inhibitory potency for two compounds. These results validate the computational protocol that allows the screening of large compound collections. One of the lead-like boronic acid derivatives identified as a covalent immunoproteasome inhibitor is a suitable starting point for chemical optimization.

Keywords: covalent inhibitor; immunoproteasome; virtual screening; β5i selective inhibitor.

MeSH terms

  • Boronic Acids / chemistry*
  • Boronic Acids / pharmacology
  • Computer Simulation
  • Drug Evaluation, Preclinical
  • Models, Molecular
  • Molecular Docking Simulation
  • Molecular Structure
  • Proteasome Inhibitors / chemistry*
  • Proteasome Inhibitors / pharmacology
  • Structure-Activity Relationship

Substances

  • Boronic Acids
  • Proteasome Inhibitors