The role of solvent-accessible surface area in determining partition coefficients

Abstract

The logarithm of the partition coefficient (log P) of low-molecular-weight organic compounds is a physicochemical parameter used extensively in structure-biological activity studies to model interactions of the compounds with nonpolar phases in vitro and in vivo. The partition coefficient can be determined between water and a number of nonpolar solvents. The most common nonpolar solvent is 1-octanol, but solvents such as benzene, carbon tetrachloride, and chloroform are frequently used as models for the nonpolar phases. The functional relationship between chemical structure and partitioning is not well-understood. In this paper, partition coefficient data for 50 solutes in six nonpolar solvent systems are analyzed by using principal components analysis. The objective of the work is to explore the relationship between solute structure and partitioning behavior for simple organic compounds. Two structural factors are found to be important, with the isotropic surface area being the most important. The isotropic surface area can be used to estimate log P in some solvents and as an independent variable in quantitative structure-activity relationships (QSAR). This is illustrated by estimating the rate of epidermal diffusion of steroids.

Multivariate analysis of hydrophobic descriptors

“…Thus, PCA of log Pvalues again results in a two-component model as in the case of the previous analyses [15,16,17,18]. The loadings a ik (Table 2) represent correlation coefficients between log P from solvent i and scores t k (Table 1).…”

“… from 28 solutes [16], 50 solutes [17], and 69 solutes [18], respectively, in six solvent-water systems (n-octanol, diethylether, chloroform, carbon tetrachloride, benzene, n-hexane)…”

“…Whereas Dove et al [15] applied the standard PCA method, diagonalization of the correlation matrix, the results of the group of Bill Dunn [16,17,18] were based on diagonalizing the matrix of cross products implied in the SIMCA software pocket.…”

“…Suitable descriptors for the identification of scores from PCA were provided by Dunn et al [16,17,18] who defined and calculated the isotropic surface area, ISA [24], of solutes as the surface of the molecule accessible to nonspecific interactions with the solvent. The surface area of the solutes involved in specific hydrogen bonds with water, HSA, was excluded from the ISA.…”

Some Modeling Issues for Protein Structure Prediction Using Evolutionary Algorithms

“…Critical investigations of the PBE are available elsewhere. (da Silva et al, 2001;de Carvalho et al, 2008) The methods based on SAS arise experimentally by the linear relation between free energy and the surface area of a solute molecule (Hermann, 1972;Valvani et al, 1976;Amidon et al, 1975;Camilleri et al, 1988;Doucette e Andren, 1987;Dunn III et al, 1987;Snow et al, 2005). In this way, this method can directly provide the free energy of solvation.…”