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

The present commentary surveys the methods for obtaining the thermodynamic parameters of the drug–receptor binding equilibrium, ÎG°, ÎH°, ÎS°, and ÎC°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 TÎS° (kJ mol−1; T = 298.15 K) = 40.3 (± 0.7) + 1.00 (±0.01) ÎH° (kJ mol−1); N = 184; r = 0.981; P < 0.0001 – which is of the form ÎH° = β · ÎS°, 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 (ÎG° = −RT ln KA = ÎH° − TÎS°) 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.