Enthalpic efficiency of ligand binding

Area of Science:

• Biochemistry
• Chemical Thermodynamics
• Drug Discovery

Background:

• Ligand-protein binding thermodynamics is crucial in drug discovery.
• Focus on the enthalpic component of binding, distinct from entropy.
• Previous studies have not fully addressed the impact of molecular size on binding enthalpy.

Purpose of the Study:

• To characterize the enthalpy contribution to ligand-protein binding.
• To investigate the relationship between molecular size and maximal achievable enthalpy.
• To introduce a size-independent metric for comparing binding efficiency.

Main Methods:

• Decomposition of the dissociation constant (pK(d)) into enthalpic (pK(H)) and entropic (pK(S)) components.
• Definition and application of pK(H) = -ΔH/(2.303·RT) to quantify enthalpy.
• Introduction of Size-Independent Enthalpic Efficiency (SIHE) = pK(H)/40·HA(0.3) for size-unbiased comparison.

Main Results:

• Maximal achievable pK(H) decreases with increasing molecular size.
• Maximal pK(d) increases with molecular size up to a plateau.
• SIHE provides a method for unbiased comparison of binding characteristics across different molecular sizes.

Conclusions:

• Simultaneous optimization of binding affinity and enthalpy becomes less feasible with increasing molecular size.
• Binding thermodynamics considerations are most impactful in hit prioritization and hit-to-lead optimization stages.
• SIHE offers a valuable tool for drug discovery programs to monitor optimization and select promising compounds.