Journal
MOLECULES
Volume 24, Issue 14, Pages -Publisher
MDPI
DOI: 10.3390/molecules24142590
Keywords
immunoproteasome; covalent inhibitor; virtual screening; beta 5i selective inhibitor
Funding
- Marie Sklodowska Curie Action (MSCA) Innovative Training Network grant FRAGNET
- National Research Development and Innovation Office [SNN_17 125496]
- Slovenian Research Agency [N1-0068 (B), P1-0208]
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Large-scale virtual screening of boronic acid derivatives was performed to identify nonpeptidic covalent inhibitors of the beta 5i 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.
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