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

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

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.

• Language: English
• Keywords: O-GlcNAc transferase, OGT inhibitors, virtual screening, pharmaceutical chemistry
• Work type: Article
• Typology: 1.01 - Original Scientific Article
• Organization: FFA - Faculty of Pharmacy
• Year: 2022
• Number of pages: 21 str.
• Numbering: Vol. 27, iss. 6, art 1996
• PID: 20.500.12556/RUL-137516-b0f223a7-0e4a-1d65-94f4-52e297b46d04
• UDC: 615.4:54
• ISSN on article: 1420-3049
• DOI: 10.3390/molecules27061996
• COBISS.SI-ID: 101699843
• Publication date in RUL: 20.06.2022

Record is a part of a journal

• Title: Molecules
• Shortened title: Molecules
• Publisher: MDPI
• ISSN: 1420-3049
• COBISS.SI-ID: 18462981

Licences

• License: CC BY 4.0, Creative Commons Attribution 4.0 International
• Link: http://creativecommons.org/licenses/by/4.0/
• Description: This is the standard Creative Commons license that gives others maximum freedom to do what they want with the work as long as they credit the author.
• Licensing start date: 19.03.2022

Secondary language

• Language: Slovenian
• Keywords: O-GlcNAc transferaza, zaviralci OGT, virtualno rešetanje, farmacevtska kemija