CommentaryCan thermodynamic measurements of receptor binding yield information on drug affinity and efficacy?
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 ΔG° is related linearly to ΔH° and ΔS° by the Gibbs equation, ΔG° = ΔH° − TΔS°, it is useful to represent the thermodynamic data of drug–receptor interaction in a −TΔS° 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 ΔG° and, as a consequence, on KA (ΔG° = −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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