A surface area approach to determination of partition coefficients

Abstract

A suite of computer programs (AMBER, MS, SURFACE, and GENSTAT) has been used t o calculate the contribution to surface area b y the component atoms of a large number of benzene derivatives containing a variety of substituents such as alkyl, hydroxy, alkoxy, amino, and carbonyl functions (ester, ketone, and aldehyde). We have also considered a wide range of polyaromatic compounds. Component surface areas were related to the measured n-octanol-water partition coefficients ( P ) of the molecules under consideration, using linear regression analysis. This surface area group contribution approach was then used to estimate the partition coefficient of other molecules, the structures of which could be defined in terms of the components that have been used in the current model for predicting log P.

Molecular Lipophilicity Potential, a tool in 3D QSAR: Method and applications

“…If spreading out lipophilicity over a given space is valid, the original logP values should be recovered by integration of the MLR Because the solvent-accessible surface should represent how the molecule is perceived by the environment, it appears to be suited well for integrating the MLP [18,19]. However, a prediction of logP can only be made if a preliminary correlation with experimental lipophilicity is established.…”

Calculation of hydrophobic parameters directly from three-dimensional structures using comparative molecular field analysis

“…Various investigators have demonstrated the existence of close correlations between the log P values of organic compounds and their molecular surface area or volume, describing their 'steric' or bulk properties plus the hydrogen-bond donating and accepting properties [43][44][45][46][47][48][49][50][51]. The H20 probe in GRID is an electrically neutral group that has a van der Waals radius of 1.70 A.…”

Measurement and prediction of hydrophobicity parameters for highly lipophilic compounds: Application of the HPLC column-switching technique to measurement of log P of diarylpyrazines

“…To solve this problem, some procedures, such as re-extraction of the aqueous phase before the measurement of concentrations and the use of radiolabeled solutes, have been used to get a satisfactory response with the detector used. 3 In addition to direct measurements, the log P value is often estimated by calculations or by retention parameters derived from reversed-phase HPLC, hereafter referred to as the HPLC method. The most widely used methodology for calculating log P was first proposed by Fujita et al, being based on an additive-constitutive, free energy related property of log P. 4 Thus, by using π defined as the difference in log P between a derivative with a given X substituent (RX) and the parent compound (RH), log P values for multisubstituted compounds might be expressed as:…”