Málstofa Lífvísindaseturs - Designing inhibitors for “undruggable” glycolysis enzymes

Málstofa Lífvísindaseturs fimmtudaginn 11. desember kl. 12:00-13:00 í Öskju, stofu N-132

Fyrirlesari: Jens Guðmundur Hjörleifsson, lektor við Líf- og umhverfisvísindadeild, Háskóla Íslands

Titill: Designing and screening inhibitors for “undruggable” glycolysis enzymes

Ágrip: Enzymes that drive central metabolism are frequently labelled “undruggable” because their active sites are often highly polar and their binding pockets poorly suited for planar, drug-like inhibitors. Yet these same enzymes are deeply intertwined with cellular growth and disease, making them intriguing but underexplored therapeutic targets.

In this project, we set out to probe the inhibition of two glycolytic enzymes, glucose-6-phosphate isomerase (GPI) and triosephosphate isomerase (TPI). Because glycolytic flux is frequently upregulated in cancer cells, selective inhibition of these enzymes could provide a route to interfere with cancer metabolism. By combining large-scale virtual screening, fragment screening, and experimental validation, we identified weak but reproducible inhibitors of these enzymes—many of which are polar, metabolite-like compounds. While our search continues, we are exploring the use of phosphate-mimicking groups to improve the pharmacokinetic potential of active-site inhibitors. In parallel, we are investigating modulatory allosteric sites using X-ray crystallography-based fragment screening.

Screening enzymes, long considered undruggable, remains a formidable challenge, but our results highlight that progress is achievable through a combinatory approach that integrates both computational and experimental strategies.

Starfsferill: Jens Guðmundur Hjörleifsson is an Assistant Professor of Biochemistry at the University of Iceland and head of the Department of Biochemistry (Lífefnfræðistofa RH). He holds a Ph.D. and B.Sc. in Biochemistry from the University of Iceland and an M.Sc. in Peptide and Protein Chemistry from Stockholm University. He oversees the Protein Science Core in Askja. His research focuses on protein structure and function, ligand binding, and the identification of small-molecule modulators of metabolic enzymes.