Can thermodynamic measurements of receptor binding yield information on drug affinity and efficacy?

Abstract

The present commentary surveys the methods for obtaining the thermodynamic parameters of the drug–receptor binding equilibrium, ΔG°, ΔH°, ΔS°, and ΔC°p (standard free energy, enthalpy, entropy, and heat capacity, respectively). Moreover, it reviews the available thermodynamic data for the binding of agonists and antagonists to several G-protein coupled receptors (GPCRs) and ligand-gated ion channel receptors (LGICRs). In particular, thermodynamic data for five GPCRs (β-adrenergic, adenosine A1, adenosine A2A, dopamine D2, and 5-HT1A) and four LGICRs (glycine, GABAA, 5-HT3, and nicotinic) have been collected and analyzed. Among these receptor systems, seven (three GPCRs and all LGICRs) show “thermodynamic agonist–antagonist discrimination”: when the agonist binding to a given receptor is entropy-driven, the binding of its antagonist is enthalpy-driven, or vice versa. A scatter plot of all entropy versus enthalpy values of the database gives a regression line with the equation TΔS° (kJ mol−1; T = 298.15 K) = 40.3 (± 0.7) + 1.00 (±0.01) ΔH° (kJ mol−1); N = 184; r = 0.981; P < 0.0001 – which is of the form ΔH° = β · ΔS°, revealing the presence of the “enthalpy–entropy compensation” phenomenon. This means that any decrease of binding enthalpy is compensated for by a parallel decrease of binding entropy, and vice versa, in such a manner that affinity constant values (KA) of drug–receptor equilibrium (ΔG° = −RT ln KA = ΔH° − TΔS°) cannot be greater than 1011 M−1. According to the most recent hypotheses concerning drug–receptor interaction mechanisms, these thermodynamic phenomena appear to be a consequence of the rearrangement of solvent molecules that occurs during the binding.