ISSN:
0020-7608
Keywords:
Computational Chemistry and Molecular Modeling
;
Atomic, Molecular and Optical Physics
Source:
Wiley InterScience Backfile Collection 1832-2000
Topics:
Chemistry and Pharmacology
Notes:
Dose-response relationships of drug-receptor binding show that receptor sites are, in many cases, singly occupied by the drug molecules. Although this single-site occupancy may be demonstrated for bound hormone analogues which inhibit, stimulate, or partially stimulate the response, the molecular occupancy of the receptor site is essentially statistical in character, and the observed binding constant may represent a sum of conformer contributions. These conformer contributions are proportionately weighted by the relevant conformer fractions of the drug and receptor for each interaction. In practice, more than one conformer may bind productively to the receptor, while, on the other hand, even within one identifiable conformation, restriction on the fraction of molecules eliciting a response could produce partial agonism. Thethermodynamic representation of explicit models of receptor interaction are reviewed taking into account the reference phase of the receptor environment and its potential heterogeneity. Decomposition of thermodynamic data for membrane-bound β-adrenoceptor agents shows that referencing the data to a hydrocarbon environment produces more comparative insight into enthalpic differences. Differences in the enthalpies of binding of the phenoxypropanolamine derivatives practolol and propranolol are largely due to loss of hydration on the amidic carbonyl moiety of practolol. Using this hydrocarbon model reference state for comparison, major differences in the enthalpies of binding of the amine moiety in phenethanolamines and phenoxypropanolamines are observed. There is a 6-7 kcal enthalpic loss in substituting a methyl group on the protonated amine moiety of noradrenaline, and a further similar loss of 6-7 kcal in substituting t-butyl for the isopropyl group. In contrast, the phenoxypropanolamine derivatives show an approximately constant mode of binding for these alkyl substituents. The possibilities that the amine moiety is sited differently in phenethanolamine and phenoxypropanolamine binding, and is multiply hydrogen bonded to three receptor sites in the natural hormone are explored. The identification of bioactive conformers in intracellular and membrane-bound receptor agents is also reviewed.
Additional Material:
10 Ill.
Type of Medium:
Electronic Resource
URL:
http://dx.doi.org/10.1002/qua.560320822
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