Discovery of immunoproteasome inhibitors using large-scale covalent virtual screening

Scarpino, 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)

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.

• Jezik: Angleški jezik
• Ključne besede: immunoproteasome, covalent inhibitor, virtual screening, β5i selective inhibitor
• Vrsta gradiva: Članek v reviji
• Tipologija: 1.01 - Izvirni znanstveni članek
• Organizacija: FFA - Fakulteta za farmacijo
• Status publikacije: Objavljeno
• Različica publikacije: Objavljena publikacija
• Leto izida: 2019
• Št. strani: 12 str.
• Številčenje: Vol. 24, iss. 14, art. 2590
• PID: 20.500.12556/RUL-132844
• UDK: 615.4:54
• ISSN pri članku: 1420-3049
• DOI: 10.3390/molecules24142590
• COBISS.SI-ID: 4765297
• Datum objave v RUL: 04.11.2021

Gradivo je del revije

• Naslov: Molecules
• Skrajšan naslov: Molecules
• Založnik: MDPI
• ISSN: 1420-3049
• COBISS.SI-ID: 18462981

Licence

• Licenca: CC BY 4.0, Creative Commons Priznanje avtorstva 4.0 Mednarodna
• Povezava: http://creativecommons.org/licenses/by/4.0/deed.sl
• Opis: To je standardna licenca Creative Commons, ki daje uporabnikom največ možnosti za nadaljnjo uporabo dela, pri čemer morajo navesti avtorja.
• Začetek licenciranja: 16.07.2019