Discovery of Immunoproteasome Inhibitors Using Large-Scale Covalent Virtual Screening
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...
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MDPI AG
2019-07-01
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| Series: | Molecules |
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| Online Access: | https://www.mdpi.com/1420-3049/24/14/2590 |
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doaj-f0617d17008e4568b5946d60186ffb702020-11-25T01:12:51ZengMDPI AGMolecules1420-30492019-07-012414259010.3390/molecules24142590molecules24142590Discovery of Immunoproteasome Inhibitors Using Large-Scale Covalent Virtual ScreeningAndrea Scarpino0Dávid Bajusz1Matic Proj2Martina Gobec3Izidor Sosič4Stanislav Gobec5György G. Ferenczy6György M. Keserű7Medicinal Chemistry Research Group, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Magyar tudósok krt. 2, H-1117 Budapest, HungaryMedicinal Chemistry Research Group, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Magyar tudósok krt. 2, H-1117 Budapest, HungaryFaculty of Pharmacy, University of Ljubljana, Aškerčeva cesta 7, SI-1000 Ljubljana, SloveniaFaculty of Pharmacy, University of Ljubljana, Aškerčeva cesta 7, SI-1000 Ljubljana, SloveniaFaculty of Pharmacy, University of Ljubljana, Aškerčeva cesta 7, SI-1000 Ljubljana, SloveniaFaculty of Pharmacy, University of Ljubljana, Aškerčeva cesta 7, SI-1000 Ljubljana, SloveniaMedicinal Chemistry Research Group, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Magyar tudósok krt. 2, H-1117 Budapest, HungaryMedicinal Chemistry Research Group, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Magyar tudósok krt. 2, H-1117 Budapest, HungaryLarge-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.https://www.mdpi.com/1420-3049/24/14/2590immunoproteasomecovalent inhibitorvirtual screeningβ5i selective inhibitor |
| collection |
DOAJ |
| language |
English |
| format |
Article |
| sources |
DOAJ |
| author |
Andrea Scarpino Dávid Bajusz Matic Proj Martina Gobec Izidor Sosič Stanislav Gobec György G. Ferenczy György M. Keserű |
| spellingShingle |
Andrea Scarpino Dávid Bajusz Matic Proj Martina Gobec Izidor Sosič Stanislav Gobec György G. Ferenczy György M. Keserű Discovery of Immunoproteasome Inhibitors Using Large-Scale Covalent Virtual Screening Molecules immunoproteasome covalent inhibitor virtual screening β5i selective inhibitor |
| author_facet |
Andrea Scarpino Dávid Bajusz Matic Proj Martina Gobec Izidor Sosič Stanislav Gobec György G. Ferenczy György M. Keserű |
| author_sort |
Andrea Scarpino |
| title |
Discovery of Immunoproteasome Inhibitors Using Large-Scale Covalent Virtual Screening |
| title_short |
Discovery of Immunoproteasome Inhibitors Using Large-Scale Covalent Virtual Screening |
| title_full |
Discovery of Immunoproteasome Inhibitors Using Large-Scale Covalent Virtual Screening |
| title_fullStr |
Discovery of Immunoproteasome Inhibitors Using Large-Scale Covalent Virtual Screening |
| title_full_unstemmed |
Discovery of Immunoproteasome Inhibitors Using Large-Scale Covalent Virtual Screening |
| title_sort |
discovery of immunoproteasome inhibitors using large-scale covalent virtual screening |
| publisher |
MDPI AG |
| series |
Molecules |
| issn |
1420-3049 |
| publishDate |
2019-07-01 |
| description |
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. |
| topic |
immunoproteasome covalent inhibitor virtual screening β5i selective inhibitor |
| url |
https://www.mdpi.com/1420-3049/24/14/2590 |
| work_keys_str_mv |
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