title: Binding thermodynamics as a tool to investigate the mechanisms of drug-receptor interactions: thermodynamics of cytoplasmic steroid/nuclear receptors in comparison with membrane receptors.
abstract: Drug-receptor binding thermodynamics has proved to be a valid tool for pharmacological and pharmaceutical characterization of molecular mechanisms of receptor-recognition phenomena. The large number of membrane receptors so far studied has led to the discovery of enthalpy-entropy compensation effects in drug-receptor binding and discrimination between agonists and antagonists by thermodynamic methods. Since a single thermodynamic study on cytoplasmic receptors was known, this paper reports on binding thermodynamics of estradiol, ORG2058, and R1881 bound to estrogen, progesterone, and androgen steroid/nuclear receptors, respectively, as determined by variable-temperature binding constant measurements. The binding at 25 degrees C appears enthalpy/entropy-driven (-53.0 </= DeltaG degrees </= -48.6, -34.5 </= DeltaH degrees </= -19.9 kJ/mol, 0.057 </= DeltaS degrees </= 0.111, and -2.4 </= DeltaC(p) degrees </= -1.7 kJ mol(-1) K(-1)) and is interpreted in terms of hydrophobic and hydrogen-bonded specific interactions. Results obtained for cytoplasmic receptors are extensively compared with those known for typical membrane receptors, in particular the adenosine A(1) receptor, to investigate the thermodynamic bases of drug-receptor binding from the most general point of view.
authors.affiliation: Centro di Strutturistica Diffrattometrica and Dipartimento di Chimica, University of Ferrara, via Borsari 46, 44100, Ferrara, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Gilli
authors.forename: Gastone
authors.initials: G
authors.lastname: Gilli
authors.forename: Pier Andrea
authors.initials: PA
authors.lastname: Borea
authors.forename: Katia
authors.initials: K
authors.lastname: Varani
authors.forename: Angelo
authors.initials: A
authors.lastname: Scatturin
authors.forename: Alessandro
authors.initials: A
authors.lastname: Dalpiaz
mesh_terms: D004958:Estradiol / Q000378:metabolism*; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D015741:Metribolone / Q000378:metabolism*; D011282:Pregnenediones / Q000378:metabolism*; D011467:Prostate / Q000378:metabolism; D011944:Receptors, Androgen / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000378:metabolism*; D011960:Receptors, Estrogen / Q000378:metabolism; D011980:Receptors, Progesterone / Q000378:metabolism; D011987:Receptors, Steroid / Q000378:metabolism*; D013816:Thermodynamics; D014599:Uterus / Q000378:metabolism
chemical_list: D011282:Pregnenediones; D011944:Receptors, Androgen; D011956:Receptors, Cell Surface; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D011987:Receptors, Steroid; C020175:16 alpha-ethyl-21-hydroxy-19-nor-4-pregnene-3,20-dione; D015741:Metribolone; D004958:Estradiol