Lipophilicity descriptors

Lipophilicity is intuitively felt to be a key parameter in predicting and interpreting permeability and thus the number of types of lipophilicity systems under study has grown enormously over the years to increase the chances of finding good mimics of biomembrane models. However, the relationship between lipophilicity descriptors and the membrane permeation process is not clear. Membrane permeation is due to two main components the partition rate constant between the lipid leaflet and the aqueous environment and the flip-flop rate constant between the two lipid leaflets in the bilayer [13]. Since the flip-flop is supposed to be rate limiting in the permeation process, permeation is determined by the partition coefficient between the lipid and the aqueous phase (which can easily be determined by log D) and the flip-flop rate constant, which may or may not depend on lipophilicity and if it does so depend, on which lipophilicity scale should it be based ... 

The Jamieson paper reports the results of a number of studies, some successful, others not. Failures can be ascribed to the difficulties encountered in log P control. The first evident trouble concerns the choice of the lipophilicity descriptor many prefer log P, but this choice is questionable as has been outlined by Lombardo (see Chapter 16). Secondly, variations in lipophilicity profile influence not only hERG activity, but also target selectivity and also ADMET properties. Lipophilicity is a bulk property and its modification can involve different moieties of the molecules. Once the chemical modulation has been designed, but before moving to the bench, the research group should predict the consequences of this change on each step of the drug s action, but unfortunately this is not always done. 

The pH-metric technique used to determine partition coefficients was first used in the 1950s in solvent extraction of metal complexes [280-282], but it is in pharmaceutical research that it is most widely used thanks to the recent development of a fully automated and computer-controlled apparatus [125,283]. The potentiometric approach has been validated in various solvent systems [284-287], and it has become a relevant and expanding experimental technique to obtain lipophilicity descriptors [257,287-289]. 

P. A., Girault, H. H., Testa, B., Combined molecular lipophilicity descriptors and their role in understanding intramolecular effects, Pharm. Sci. Technol. Today 1999, 2, 327-335. 

The major hurdle to overcome in the development of 3D-QSAR models using steric, electrostatic, or lipophilic fields is related to both conformation selection and subsequent suitable overlay (alignment) of compounds. Therefore, it is of some interest to provide a conformation-ally sensitive lipophilicity descriptor that is alignment-independent. In this chapter we describe the derivation and parametrization of a new descriptor called 3D-LogP and demonstrate both its conformational sensitivity and its effectiveness in QSAR analysis. The 3D-LogP descriptor provides such a representation in the form of a rapidly computable description of the local lipophilicity at points on a user-defined molecular surface. 

The chapter is divided into three sections the first part is concerned with the derivation of 3D-LogP descriptor and the selection of suitable parameters for the computation of the MLP values. This study was performed on a set of rigid molecules in order, at least initially, to avoid the issue of conformation-dependence. In the second part, both the information content and conformational sensitivity of the 3D-LogP description was established using a set of flexible acetylated amino acids and dipeptides. This initial work was carried out using log P as the property to be estimated/predicted. However, it should be made clear that, while the 3D-LogP descriptor can be used for the prediction of log P, this was not the primary intention behind its the development. Rather, as previously indicated, the rationale for this work was the development of a conformationally sensitive but alignment-free lipophilicity descriptor for use in QSAR model development. The use of log P as the property to be estimated/predicted enables one to establish the extent of information loss, if any, in the process used to transform the results of MLP calculations into a descriptor suitable for use in QSAR analyses. 

Tab. 5.5 Inhibitory activity (/C50, uM) of 3-OCH3, 4-alkoxy-benzylpyrimidines (x= 1-6) in cell-free and whole cell systems of coli ATCC 11 775 (TMP sensitive) and . coli RT 500 (TMP resistant) and the lipophilicity descriptor log /7r. (Reprinted from Tab. 2 ref. 39)...

Lipophilicity descriptors, in particular, the atomic lipophilicity contribution La in Ghose and Crippen s system, taking into account the environment of an atom, and group lipophilicity Lg defined as a sum of contributions for a non-hydrogen atom and attached hydrogens. 

Broto-Moreau-Vandicke hydrophobic atomic constants -> lipophilicity descriptors... 

Calculated LOGP - lipophilicity descriptors O Leo-Hansch hydrophobic fragmental constants)... 

CASE approach - lipophilicity descriptors (O Klopman hydrophobic models)... 

Dunn model based on surface area -> lipophilicity descriptors Di/index - multiple bond descriptors... 

---