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Open AccessArticle

Discovery of Immunoproteasome Inhibitors Using Large-Scale Covalent Virtual Screening

1
Medicinal Chemistry Research Group, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Magyar tudósok krt. 2, H-1117 Budapest, Hungary
2
Faculty of Pharmacy, University of Ljubljana, Aškerčeva cesta 7, SI-1000 Ljubljana, Slovenia
*
Author to whom correspondence should be addressed.
Academic Editor: Sandra Gemma
Molecules 2019, 24(14), 2590; https://doi.org/10.3390/molecules24142590
Received: 20 June 2019 / Revised: 9 July 2019 / Accepted: 12 July 2019 / Published: 16 July 2019
(This article belongs to the Special Issue Structure-Based Design of Biologically Active Compounds)
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. View Full-Text
Keywords: immunoproteasome; covalent inhibitor; virtual screening; β5i selective inhibitor immunoproteasome; covalent inhibitor; virtual screening; β5i selective inhibitor
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MDPI and ACS Style

Scarpino, A.; Bajusz, D.; Proj, M.; Gobec, M.; Sosič, I.; Gobec, S.; Ferenczy, G.G.; Keserű, G.M. Discovery of Immunoproteasome Inhibitors Using Large-Scale Covalent Virtual Screening. Molecules 2019, 24, 2590.

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