Thermodynamics of ligand binding and efficiency

Area of Science:

• Biochemistry
• Computational Chemistry
• Drug Discovery

Background:

• Understanding protein-ligand binding thermodynamics is crucial for drug discovery.
• Computational structure-based design frequently utilizes interaction energies, approximating enthalpy, to predict binding affinity.

Purpose of the Study:

• To analyze experimental binding thermodynamics for ~100 protein-ligand complexes.
• To investigate the relationship between enthalpy, entropy (-TΔS), and free energy (ΔG) of binding.
• To assess the implications for computational drug design strategies.

Main Methods:

• Analysis of experimental binding thermodynamics data for a diverse set of protein-ligand complexes.
• Correlation analysis of enthalpy, -TΔS, and ΔG.
• Examination of ligand efficiency trends with respect to molecular size.

Main Results:

• A clear correlation between enthalpy and -TΔS was observed.
• Ligand affinity (ΔG) generally showed no correlation with enthalpy or -TΔS.
• Enthalpy, not entropy, primarily drives trends in ligand efficiency related to molecular size.

Conclusions:

• The lack of general correlation between ΔG and enthalpy/-TΔS poses challenges for structure-based drug design relying on enthalpy approximations.
• Specific protein-ligand interactions may exhibit enthalpy-free energy correlations, potentially explaining modeling success for certain targets.
• Enthalpic contributions are key to understanding ligand efficiency variations with molecular size.