Enhanced Binding Affinity of 2-Deoxyglucose-6Phosphate to Hexokinase I: Insights from Molecular Simulations

• DOI: 10.20944/preprints202411.2341.v1
• Publication Date: 2024-12-02T02:00:11Z
• Authors: Yifan He; Haotian Liu; Qianyi Shi; Leyao Xu; Junming Feng; Chunxin Xu; Yan Qu; Bowen Meng; Xiaoyi Lai; Xingchen Liu; Shoucheng Chen; Yang Cao
• Keywords: Deoxyglucose; Hexokinase

2-deoxyglucose (2-DG), targeting Hexokinase I (HKI) to inhibit glycolysis in cancer cells, has inspired drug design. Increasing evidence suggests that its phosphorylated form, 2-deoxyglucose-6-phosphate (2-DG-6-P), may HKI more effectively, highlighting the need understand molecular mechanisms behind this effect. Using simulations, we examined interactions between and substrates—glucose (G) glucose-6-phosphate (G-6-P)—and inhibitors—2-DG 2-DG-6-P. G G-6-P showed stable with HKI, involving residues like ILE 662, SER 588, PRO 590, while 2-DG had less interactions. However, 2-DG-6-P formed most complex, engaging additional such as VAL 663 THR 848, enhanced binding through hydrophobic hydrogen bond facilitated by group. This study reveals differential effects of on inhibition, unique mechanism post-phosphorylation supporting development targeted inhibitors exploit cell metabolism.