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Highly potent bisphosphonate ligands for phosphoglycerate kinase
D L Jakeman1, A J Ivory, M P Williamson
1Krebs Institute, Department of Chemistry, University of Sheffield, Sheffield, S3 7HF, UK.
Journal of Medicinal Chemistry
|November 7, 1998
Summary
Researchers created stable mimics of a key glycolysis intermediate, 1,3-bisphospho-D-glyceric acid (1,3-BPG). Fluorinated analogs significantly enhanced binding to phosphoglycerate kinase (PGK), acting as potent enzyme inhibitors.
Area of Science:
- Biochemistry
- Enzyme Inhibitor Development
- Metabolic Pathway Research
Background:
- 1,3-bisphospho-D-glyceric acid (1,3-BPG) is a crucial intermediate in glycolysis.
- Understanding its interaction with phosphoglycerate kinase (PGK) is vital for metabolic studies.
- Existing substrate analogs may lack stability or optimal binding characteristics.
Purpose of the Study:
- To synthesize novel, stable analogs of 1,3-BPG.
- To evaluate the binding affinity of these analogs to phosphoglycerate kinase (PGK).
- To identify structural modifications that enhance ligand-target interactions.
Main Methods:
- Synthesis of 1,3-BPG analogs using nonscissile methanephosphonic acids.
- Incorporation of fluorine substitutions into the alpha-methylene groups of the analogs.
- Binding affinity assessment using Nuclear Magnetic Resonance (NMR) spectroscopy.
Main Results:
- Novel, stable mimics of 1,3-BPG were successfully synthesized.
- Fluorine substitution significantly enhanced the binding of analogs to PGK.
- The best-performing analogs exhibited 50-100 fold stronger binding than the natural substrate.
Conclusions:
- Fluorinated methanephosphonate analogs represent potent, stable mimics of 1,3-BPG.
- These analogs demonstrate significantly improved binding to phosphoglycerate kinase (PGK).
- Ligand design for PGK inhibition should consider low pKa3 values and potentially beta-carbonyl presence.