Discovery of a new drug-like series of OGT inhibitors by virtual screening

Loi, Elena Maria (avtor), Tomašič, Tihomir (avtor), Balsollier, Cyril (avtor), van Eekelen, Kevin (avtor), Weiss, Matjaž (avtor), Gobec, Martina (avtor), Alteen, Matthew G (avtor), Vocadlo, David J. (avtor), Pieters, Roland J. (avtor), Anderluh, Marko (avtor)

O-GlcNAcylation is an essential post-translational modification installed by the enzyme O-β-N-acetyl-d-glucosaminyl transferase (OGT). Modulating this enzyme would be extremely valuable to better understand its role in the development of serious human pathologies, such as diabetes and cancer. However, the limited availability of potent and selective inhibitors hinders the validation of this potential therapeutic target. To explore new chemotypes that target the active site of OGT, we performed virtual screening of a large library of commercially available compounds with drug-like properties. We purchased samples of the most promising virtual hits and used enzyme assays to identify authentic leads. Structure-activity relationships of the best identified OGT inhibitor were explored by generating a small library of derivatives. Our best hit displays a novel uridine mimetic scaffold and inhibited the recombinant enzyme with an IC50 value of 7 µM. The current hit represents an excellent starting point for designing and developing a new set of OGT inhibitors that may prove useful for exploring the biology of OGT.

• Jezik: Angleški jezik
• Ključne besede: O-GlcNAc transferase, OGT inhibitors, virtual screening, pharmaceutical chemistry
• Vrsta gradiva: Članek v reviji
• Tipologija: 1.01 - Izvirni znanstveni članek
• Organizacija: FFA - Fakulteta za farmacijo
• Leto izida: 2022
• Št. strani: 21 str.
• Številčenje: Vol. 27, iss. 6, art 1996
• PID: 20.500.12556/RUL-137516-b0f223a7-0e4a-1d65-94f4-52e297b46d04
• UDK: 615.4:54
• ISSN pri članku: 1420-3049
• DOI: 10.3390/molecules27061996
• COBISS.SI-ID: 101699843
• Datum objave v RUL: 20.06.2022

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: 19.03.2022

Sekundarni jezik

• Jezik: Slovenski jezik
• Ključne besede: O-GlcNAc transferaza, zaviralci OGT, virtualno rešetanje, farmacevtska kemija