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Developing high affinity oligosaccharide inhibitors: conformational pre-organization paired with functional group
Robert S McGavin1, David R Bundle
1Alberta Ingenuity Centre for Carbohydrate Science, Department of Chemistry, University of Alberta, Edmonton, Alberta T6G 2G2, Canada.
Organic & Biomolecular Chemistry
|July 21, 2005
Summary
Researchers explored intramolecular tethering and functional group modification to create high-affinity oligosaccharide ligands. While tethering constrained the trisaccharide, combining it with functional group changes did not yield additive binding affinity gains as expected.
Area of Science:
- Carbohydrate chemistry
- Biophysical chemistry
- Computational chemistry
Background:
- Intramolecular tethering can constrain oligosaccharides into bioactive conformations.
- Previous work demonstrated a 15-fold affinity increase by tethering a trisaccharide.
- Functional group modifications are explored to further enhance ligand binding affinity.
Purpose of the Study:
- To synthesize and evaluate beta-alanyl tethered trisaccharide derivatives with monochlorination and monodeoxygenation.
- To assess if combining tethering with functional group modifications leads to additive binding affinity enhancements.
- To investigate the binding parameters and conformational effects of these modified ligands.
Main Methods:
- Synthesis of beta-alanyl tethered trisaccharide derivatives.
- Isothermal titration calorimetry (ITC) for binding parameter measurement.
- Molecular dynamics (MD) calculations and docking analysis for rationalization.
Main Results:
- Two novel beta-alanyl tethered trisaccharide derivatives were synthesized.
- Isothermal titration calorimetry revealed binding parameters for the new ligands.
- Molecular dynamics and docking analyses provided insights into binding interactions.
- The combined strategies of tethering and functional group modification did not result in additive free energy gains.
Conclusions:
- Beta-alanyl tethering is a viable strategy for constraining trisaccharides.
- The assumption of additive free energy changes when pairing tethering with functional group modification is incorrect.
- In some cases, functional group modification in conjunction with tethering can be counter-productive to binding affinity.