Líffræðifélag Íslands - biologia.is
Líffræðiráðstefnan 2023
Höfundar / Authors: Yiming Yang Jónatansdóttir and Jens G. Hjörleifsson
Starfsvettvangur / Affiliations: Science Institute, University of Iceland, Department of Biochemistry
Kynnir / Presenter: Jens G. Hjörleifsson
Allostery is an efficient mechanism where protein activity/function is modulated by the binding of ligands to non-active sites. Finding allosteric sites is of great interest to drug discovery, as such sites are less conserved among homologous proteins, making selective targeting possible. Also, ligands that act on allosteric sites do not compete with endogenous substrates. Most allosteric sites to date have been discovered serendipitously via screening. It can be presumed that all enzymes have allosteric sites that are hidden under steady-state or in the absence of effector molecules. If such cryptic sites do exist, it might only be occupied when certain metabolites are abnormally enhanced, or when exogenous binders are present. Here, we intend to identify new allosteric interactions between metabolites and several human glycolytic enzymes, with the hope of developing modulators that hamper tumor growth via glycolysis inhibition. Our targets of interest include glucose-6-phosphate isomerase (GPI) and triosephosphate isomerase (TPI). Screening of hits has been performed on metabolite libraries against our targets using both biophysical and activity-based methods. We have screened ~800 compounds against GPI, 12 of which appeared to be weak modulators. Once knowing the modes of action and binding sites of the hits, we will use a computational strategy to identify and/or design compounds displaying good inhibitory activity against the targets.