1. Discovery of a New Drug-like Series of OGT Inhibitors by Virtual Screening
- Author
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Loi, Elena M, Tomašič, Tihomir, Balsollier, Cyril, van Eekelen, Kevin, Weiss, Matjaž, Gobec, Martina, Alteen, Matthew G, Vocadlo, David J, Pieters, Roland J, Anderluh, Marko, Afd Chemical Biology and Drug Discovery, Chemical Biology and Drug Discovery, Afd Chemical Biology and Drug Discovery, and Chemical Biology and Drug Discovery
- Subjects
Pharmaceutical Science ,Farmacevtska kemija ,N-Acetylglucosaminyltransferases ,Analytical Chemistry ,Structure-Activity Relationship ,udc:615.4:54 ,Drug Discovery ,Humans ,virtualno rešetanje ,Physical and Theoretical Chemistry ,udc:615.4 ,zaviralci OGT ,O-GlcNAc transferaza ,Research ,O-GlcNAc transferase, OGT inhibitors, virtual screening ,Organic Chemistry ,virtual screening ,pharmaceutical chemistry ,O-GlcNAc transferase ,OGT inhibitors ,Chemistry (miscellaneous) ,farmacevtska kemija ,Molecular Medicine ,O-GlcNAc transferaza, zaviralci OGT, virtualno rešetanje ,Protein Processing, Post-Translational - Abstract
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. Nasl. z nasl. zaslona. Opis vira z dne 21. 3. 2022. Št. članka: 1996. Bibliografija: str. 19-21. Abstract. ARRS European Union’s Horizon2020, projekt
- Published
- 2022