Discovery of immunoproteasome inhibitors using large-scale covalent virtual screeningScarpino, Andrea (Avtor) Bajusz, Dávid (Avtor) Proj, Matic (Avtor) Gobec, Martina (Avtor) Sosič, Izidor (Avtor) Gobec, Stanislav (Avtor) Ferenczy, György G. (Avtor) Keserü M., György (Avtor) immunoproteasomecovalent inhibitorvirtual screeningβ5i selective inhibitorLarge-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.20192021-11-04 13:40:57Članek v reviji132844UDK: 615.4:54ISSN pri članku: 1420-3049DOI: 10.3390/molecules24142590COBISS_ID: 4765297sl