Discovery of immunoproteasome inhibitors using large-scale covalent virtual screening

Andrea Scarpino, Dávid Bajusz, Matic Proj, Martina Gobec, Izidor Sosič, Stanislav Gobec, György G. Ferenczy, György M. Keser u

Research output: Contribution to journalArticle

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.

Original languageEnglish
Article number2590
JournalMolecules
Volume24
Issue number14
DOIs
Publication statusPublished - Jul 16 2019

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Keywords

  • Covalent inhibitor
  • Immunoproteasome
  • Virtual screening
  • β5i selective inhibitor

ASJC Scopus subject areas

  • Analytical Chemistry
  • Chemistry (miscellaneous)
  • Molecular Medicine
  • Pharmaceutical Science
  • Drug Discovery
  • Physical and Theoretical Chemistry
  • Organic Chemistry

Cite this

Scarpino, A., Bajusz, D., Proj, M., Gobec, M., Sosič, I., Gobec, S., Ferenczy, G. G., & Keser u, G. M. (2019). Discovery of immunoproteasome inhibitors using large-scale covalent virtual screening. Molecules, 24(14), [2590]. https://doi.org/10.3390/molecules24142590