Receptor binding thermodynamics as a tool for linking drug efficacy and affinity

Area of Science:

• Pharmacology and Thermodynamics
• Biophysics and Molecular Interactions

Background:

• Radiochemical specific binding assays determine drug-receptor binding constants (KA, KD).
• These assays calculate standard free energy (ΔG°) but not its enthalpy (ΔH°) and entropy (ΔS°) components.
• ΔH° and ΔS° provide crucial insights into drug-receptor interactions and solvent interplay.

Purpose of the Study:

• To explore the significance of enthalpy and entropy in drug-receptor binding thermodynamics.
• To investigate 'thermodynamic discrimination' as a method for classifying drug effects.
• To analyze thermodynamic binding data for G-protein coupled receptors (GPCRs) and ligand-gated ion channel receptors (LGICRs).

Main Methods:

• Analysis of existing radiochemical binding assay data.
• Thermodynamic analysis of binding equilibria to determine ΔH° and ΔS°.
• Comparison of binding thermodynamics across different receptor families (GPCRs, LGICRs).

Main Results:

• Thermodynamic discrimination, where binding is enthalpy-driven or entropy-driven, is observed.
• This phenomenon has been confirmed for adenosine receptors and is newly reported for LGICRs.
• All investigated LGICRs exhibit thermodynamic discrimination.

Conclusions:

• Thermodynamic discrimination offers a method to understand how drugs modulate signaling pathways.
• While explanations for GPCRs are elusive, LGICR discrimination may relate to solvent rearrangements and channel gating.
• Further investigation into the molecular basis of thermodynamic discrimination is warranted.