title: 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, DeltaG degrees, DeltaH degrees, DeltaS degrees, and DeltaC degrees (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 (beta-adrenergic, adenosine A(1), adenosine A(2A), dopamine D(2), and 5-HT(1A)) and four LGICRs (glycine, GABA(A), 5-HT(3), 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 TDeltaS degrees (kJ mol(-1); T = 298.15 K) = 40.3 (+/- 0.7) + 1.00 (+/-0.01) DeltaH degrees (kJ mol(-1)); N = 184; r = 0.981; P < 0.0001 - which is of the form DeltaH degrees = beta. DeltaS degrees, 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 (K(A)) of drug-receptor equilibrium (DeltaG degrees = -RT ln K(A) = DeltaH degrees - TDeltaS degrees ) cannot be greater than 10(11) 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.
authors.affiliation: Dipartimento di Medicina Clinica e Sperimentale-Sezione di Farmacologia, 44100, Ferrara, Italy. bpa@ifeuniv.unife.it
authors.forename: P A
authors.initials: PA
authors.lastname: Borea
authors.forename: A
authors.initials: A
authors.lastname: Dalpiaz
authors.forename: K
authors.initials: K
authors.lastname: Varani
authors.forename: P
authors.initials: P
authors.lastname: Gilli
authors.forename: G
authors.initials: G
authors.lastname: Gilli
mesh_terms: D000818:Animals; D058785:GABA-A Receptor Agonists; D058787:GABA-A Receptor Antagonists; D019204:GTP-Binding Proteins / Q000378:metabolism; D006801:Humans; D007473:Ion Channels / Q000378:metabolism*; D008024:Ligands; D058906:Purinergic P1 Receptor Agonists; D058915:Purinergic P1 Receptor Antagonists; D011943:Receptors, Adrenergic, beta / Q000187:drug effects / Q000378:metabolism; D011955:Receptors, Drug / Q000378:metabolism*; D011963:Receptors, GABA-A / Q000378:metabolism; D018009:Receptors, Glycine / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D018047:Receptors, Purinergic P1 / Q000378:metabolism; D013816:Thermodynamics
chemical_list: D058785:GABA-A Receptor Agonists; D058787:GABA-A Receptor Antagonists; D007473:Ion Channels; D008024:Ligands; D058906:Purinergic P1 Receptor Agonists; D058915:Purinergic P1 Receptor Antagonists; D011943:Receptors, Adrenergic, beta; D011955:Receptors, Drug; D011963:Receptors, GABA-A; D018009:Receptors, Glycine; D018047:Receptors, Purinergic P1; D019204:GTP-Binding Proteins