Elsevier

Biochemical Pharmacology

Volume 60, Issue 11, 1 December 2000, Pages 1549-1556
Biochemical Pharmacology

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

https://doi.org/10.1016/S0006-2952(00)00368-3Get rights and content

Abstract

The present commentary surveys the methods for obtaining the thermodynamic parameters of the drug–receptor binding equilibrium, ΔG°, ΔH°, ΔS°, and Δp (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.

Section snippets

Methods of thermodynamic measurements of drug–receptor interactions

GPCRs and LGICRs are membrane receptors, and, as a consequence, their concentrations are extremely low in biological tissues (typically 1–10 fmol/mg tissue) [30]. This situation has so far hampered any direct microcalorimetric determination of ΔH° for the drug–receptor equilibrium. Nevertheless, methods based on KD measurements over a range of temperatures combined with van’t Hoff analysis or other similar plots have been applied successfully to obtain the terms of the Gibbs equation. The

How can δG°, δH°, and δS° data be represented?

Since Δ is related linearly to Δ and Δ by the Gibbs equation, Δ = Δ − TΔ, it is useful to represent the thermodynamic data of drug–receptor interaction in a −TΔ versus ΔH° plot, as shown in FIG. 1, FIG. 2. Several advantages can be achieved by this type of representation:

  • 1.

    The plot allows one to obtain further information on Δ and, as a consequence, on KAG° = −RT ln KA). In fact, the same values of ΔG° (and therefore of KA) can be produced by all the linear combinations of

GPCRs

Table 1reports the thermodynamic data for the five GPCRs which have been studied so far at a reasonable level of accuracy from a thermodynamic point of view. The ranges of ΔG°, ΔH°, and −TΔS° values of both agonists and antagonist binding are given together with a qualitative classification of the prevailing EDF.

Only three of the five GPCRs reported in Table 1 are actually discriminated. This is clearly shown in Fig. 1, which summarizes in the form of −TΔS° versus ΔH° plots the results of the

Discussion

The regression equation (3) has been obtained by plotting standard enthalpy and entropy data of 184 independent experiments performed on nine different membrane receptor systems, belonging to the GPCR and LGICR families. This equation is of the form ΔH° = β · ΔS°, which is expected for a case of enthalpy–entropy compensation 35, 36, 37, 38, 39 with a compensation temperature β of 298 K. The correlation confines all affinity constant values in the region between the two diagonal dashed lines

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