Abstract
Experimental data on the affinity of various substances to albumin are essential for the development of empirical models to predict plasma binding of drug candidates. Binding of 24 substituted benzoic acid anions to bovine serum albumin was studied using spectrofluorimetric titration. The equilibrium constants of binding at 298 K were determined according to 1:1 complex formation model. The relationships between the ligand structure and albumin affinity are analyzed. The binding constant values for m- and p-monosubstituted acids show a good correlation with the Hammett constants of substituents. Two- and three-parameter quantitative structure–activity relationship (QSAR) models with theoretical molecular descriptors are able to satisfactorily describe the obtained values for the whole set of acids. It is shown that the electron-density distribution in the aromatic ring exerts crucial influence on the albumin affinity.
Highlights
Experimental in vivo study of plasma protein binding is an important step in development of novel drug substances
The same trend of decrease of K values in a row for 2-hydroxy > 3-hydroxy > 4-hydroxybenzoic acid observed in the present work and in two previous studies [9,11] provides some evidence of the consistency of results, but consideration of the structure–affinity relationships should be limited to the data obtained using exactly the same experimental procedure
Binding constants of substituted benzoic acids to BSA are sensitive to the nature and position of the substituents
Summary
Experimental in vivo study of plasma protein binding is an important step in development of novel drug substances. The strength of binding affects the distribution of a drug in the body along with its pharmacodynamic parameters, biological activity and toxicity [1]. The most abundant protein in blood plasma is serum albumin. It can be extracted from plasma and used to study binding processes in vitro. In such experiments, the strength of binding is characterized quantitatively using thermodynamic binding constants. The measured values of these constants can be used to estimate the fractions of plasma-bound and free drug in the blood, which helps to reduce the number of costly in vivo experiments [2]
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