Virtual Screening and Biochemical Testing of Borocycles as Immunoproteasome Inhibitors

Authors

  • Levente Kollár
    Affiliation

    Medicinal Chemistry Research Group, Research Centre for Natural Sciences, H-1117 Budapest, 2 Magyar tudósok krt., Hungary

  • György Gábor Frenczy
    Affiliation

    Medicinal Chemistry Research Group, Research Centre for Natural Sciences, H-1117 Budapest, 2 Magyar tudósok krt., Hungary

  • Matic Proj
    Affiliation

    Faculty of Pharmacy, University of Ljubljana, SI-1000 Ljubljana, 7 Aškerčeva cesta, Slovenia

  • Martina Gobec
    Affiliation

    Faculty of Pharmacy, University of Ljubljana, SI-1000 Ljubljana, 7 Aškerčeva cesta, Slovenia

  • Stanislav Gobec
    Affiliation

    Faculty of Pharmacy, University of Ljubljana, SI-1000 Ljubljana, 7 Aškerčeva cesta, Slovenia

  • Izidor Sosič
    Affiliation

    Faculty of Pharmacy, University of Ljubljana, SI-1000 Ljubljana, 7 Aškerčeva cesta, Slovenia

  • György Keserű
    Affiliation

    Medicinal Chemistry Research Group, Research Centre for Natural Sciences, H-1117 Budapest, 2 Magyar tudósok krt., Hungary

https://doi.org/10.3311/PPch.17202

Abstract

Inhibition of the immunoproteasome (iCP) offers new opportunities in the treatment of cancer, autoimmune disorders and neurodegenerative diseases. Inspired by the success of boronic acids as proteasome inhibitors we have complied a virtual library of commercially available 5- and 6-membered borocycles and performed a structure based virtual screening against the chymotrypsin-like (β5i) subunit of the iCP. The top scored docking poses were visually inspected to select compounds for experimental testing. Six compounds with 5-membered ring and another six compounds with 6-membered ring were subjected to biochemical tests. All compounds exhibited detectable inhibitory activity at 100 µM concentration and these are the first reported cyclic boronic acid inhibitors of the iCP. Structural variations including the ring size and the substitution of the borocyles and the substitution pattern of the attached aromatic ring resulted in no major variation of the inhibitory activity. We propose that the evaluation of larger cycling boronic acid libraries is needed to fully elucidate the potential of these structures.

Keywords:

immunoproteasome, virtual screening, biochemical testing, borocycles

Published Online

2021-05-31

How to Cite

Kollár, L., Frenczy, G. G., Proj, M., Gobec, M., Gobec, S., Sosič, I., Keserű, G. “Virtual Screening and Biochemical Testing of Borocycles as Immunoproteasome Inhibitors”, Periodica Polytechnica Chemical Engineering, 65(3), pp. 292–298, 2021. https://doi.org/10.3311/PPch.17202

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Articles