Atomic Lipophilicity Parameters

Most of the methods that are used to predict logP values of molecules depend on fragmental codes or lipophilicity increments based on extended atom types. Obviously, it is possible to assign lipophilicity increments directly to every atom of a structure as an atomic property. The distribution of lipophilic and hydrophilic properties in a molecule can be described in this way [53]. 

The substructure descriptors compare every structure with a limited set of predefined substructures. To include every important structural element, the number of substructures considered must be very high. 

Other topological descriptors do not display this disadvantage, because their definition is more general and it is possible to describe arbitrary structural patterns with the same descriptors. All topological descriptors are calculated based on the cormectivity matrix of a molecule. This matrix includes aU information about all atom-atom bonds (the so-called topology). 

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Sets of atom properties, such as point charges, atomic lipophilicity parameters or any other atom properties, can be used to describe properties of molecules. However, the use of such single atom properties as descriptors requires an atom-to-atom mapping of all atoms considered of all compounds of the dataset. This is not possible in most cases and, therefore, it is necessary to compute more general descriptors from these parameters ... 

A modification of the atomic approach was also proposed by Gaillard et al. using molecular lipophilicity potential (MLP) as a 3D source of two lipophilicity parameters calculated from the water-accessible surface, namely a hydrophobic parameter expressed as the sum ofthe positive lipophilicity potential (EM LP+) and a polar parameter expressed as the sum of the negative lipophilicity potential (EMLP—)... 

Generally, it was stated that the most significant correlation was found between the values of Pmw and po lipophilic parameters and logPRowwin calculated from atom/fragmental contribution values. MlogP correlates with the above-mentioned lipophilic parameters slightly worse than logPRowwin does (r > 0.90). It was found that... 

Analysis of the Hansch descriptors illustrates that increasing the lipophilicity property for this series of compounds will increase the bioactivity in a more dramatic fashion than increasing the Tafts steric parameter. Increasing the water accessible surface area (MOE descriptor) will increase the bioactivity of the compounds. But there is more than just adding lipophilicity and water accessible surface area to the molecules to increase binding affinity. A comparison of the substituents to the bioactivities illustrates that the bulkier X and Y groups increase bioactivity in conjunction with atomic partial charge distribution of the substituents. 

The latter free energy can be represented as a surface integral over the solvent accessible surface of the molecule on the basis of a local free energy surface density (FESD) p. This surface density function is represented in terms of a three-dimensional scalar field which is comprised of a sum of atomic increment functions to describe lipophilicity in the molecular environment.The empirical model parameters are obtained by a least squares procedure with experimental log P values as reference data. It is found that the procedure works not only for the prediction of unknown partition coefficients but also for the localization and quantification of the contribution of arbitrary fragments to this quantity. In addition, the... 

A lipophilicity model based on atomic charges, surface areas, dipole moments, and a set of adjustable parameters depending only on the atomic number [Kantola et al., 1991]. The parameter values are determined in order to reproduce experimental logP values using the following general model ... 

The same procedure is used to compute cross-correlation coefficients C, which correlate two different properties, e.g., electrostatic and lipophilic single atom parameters. Every C value describes typical distances of regions in a molecule with... 

Since the lipophilic character was found important for physiological dispositions of barbiturates, several workers investigated the relationship between partition coefficient and structural parameters (Taft s polar and steric substituents constants, number of C-atoms) of these compounds.548,549 Partitioning of barbiturates was also proved to be a significant factor for their... 

It is a popular lore that the introduction of some fluorine atoms or a short perfluoroalkyl group results in increasing lipophilicity. A classical parameter 8, Hildebrand s solubility parameter, which is the square root of the cohesive energy density, has been used for miscibility estimation [2]. If two liquids have similar values for 8, i.e. if (Si —S2)2 is small, they are miscible. 

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