Jennifer Walker, Durrant Lab
Targeting aerobic glycolysis through yeast lab evolution and computer-aided drug design (CADD).
Unregulated metabolic pathways are a distinguishing feature of cancer cells. Aerobic glycolysis is performed in malignant cancer cells even when oxygen is present and oxidative phosphorylation would be much more energetically efficient. The goal is not ATP production, but instead making important precursors required for proliferation, such as nucleotides, lipids, and amino acids. Current cancer treatments that target aerobic glycolysis are plagued with off-target effects because glycolysis shares intermediates with other pathways such as the pentose phosphate pathway (PPP). Investigating the ligand-protein interactions that drive glycolysis could aid in the design of compounds that target aerobic glycolysis specifically. Using a yeast lab evolution/target identification assay, we evolve resistance to 2-deoxyglucose (2DG), a glucose analog with anti-cancer properties. All five evolved strains had identical mutations in the expected protein target, hexokinase II (HXK2-G238V). We will use molecular dynamics simulations and virtual screening to study the effects of this mutation. We will perform additional lab evolution assays in parallel to target other important enzymes in glycolysis: phosphofructokinase I (PFK1) and pyruvate kinase (PYK). By learning more about the biophysics of these three important enzyme-ligand interactions, we aim to design more specific compounds that target this pathway with minimal off-target effects
Friday, November 30th
A219B Langley Hall