Discovery of immunoproteasome inhibitors using large-scale covalent virtual screening

Scarpino, Andrea (author), Bajusz, Dávid (author), Proj, Matic (author), Gobec, Martina (author), Sosič, Izidor (author), Gobec, Stanislav (author), Ferenczy, György G. (author), Keserü M., György (author)

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.

• Language: English
• Keywords: immunoproteasome, covalent inhibitor, virtual screening, β5i selective inhibitor
• Work type: Article
• Typology: 1.01 - Original Scientific Article
• Organization: FFA - Faculty of Pharmacy
• Publication status: Published
• Publication version: Version of Record
• Year: 2019
• Number of pages: 12 str.
• Numbering: Vol. 24, iss. 14, art. 2590
• PID: 20.500.12556/RUL-132844
• UDC: 615.4:54
• ISSN on article: 1420-3049
• DOI: 10.3390/molecules24142590
• COBISS.SI-ID: 4765297
• Publication date in RUL: 04.11.2021

Record is a part of a journal

• Title: Molecules
• Shortened title: Molecules
• Publisher: MDPI
• ISSN: 1420-3049
• COBISS.SI-ID: 18462981

Licences

• License: CC BY 4.0, Creative Commons Attribution 4.0 International
• Link: http://creativecommons.org/licenses/by/4.0/
• Description: This is the standard Creative Commons license that gives others maximum freedom to do what they want with the work as long as they credit the author.
• Licensing start date: 16.07.2019