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Updated: Jun 13, 2026
06:17
Covalent Fragment Screening Using the Quantitative Irreversible Tethering Assay
Published on: February 28, 2025
Entropic contribution to the linking coefficient in fragment based drug design: a case study
Valentina Borsi1, Vito Calderone, Marco Fragai
1Magnetic Resonance Center (CERM), University of Florence, Florence, Italy.
Journal of Medicinal Chemistry
|April 27, 2010
Summary
Tethering weak binding ligands can enhance drug discovery. This study demonstrates a case where the linking coefficient, a measure of this enhancement, is exceptionally small and purely entropic.
Area of Science:
- Medicinal Chemistry
- Chemical Biology
- Drug Discovery
Background:
- Tethering weak binding ligands is a strategy to develop potent drug leads.
- The linking coefficient (E) quantifies the binding enhancement achieved by tethering ligands.
- This enhancement is often attributed to entropic gains from tethering.
Purpose of the Study:
- To investigate a specific case study of tethered ligands with a remarkably small linking coefficient.
- To demonstrate the entropic origin of the observed binding enhancement.
Main Methods:
- Analysis of dissociation constants for individual ligands and the tethered construct.
- Calculation of the linking coefficient (E).
- Thermodynamic analysis to confirm the entropic contribution.
Main Results:
- A strikingly small linking coefficient (E = 2.1 x 10(-3) M(-1)) was observed.
- The binding enhancement in this case was shown to be entirely entropic in nature.
Conclusions:
- The study provides a clear demonstration of a purely entropic contribution to binding affinity in tethered ligands.
- Understanding such entropic effects is crucial for optimizing drug design strategies using ligand tethering.
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