Lipophilicity and Receptor Affinity

The relevance of lipophilicity in pharmacodynamics is due to the fact that inter-and intramolecular interactions governing lipophiUcity (Sections 12.1.1.2 and 12.1.1.3) are of the same nature as those that govern drug recognition and binding to biological sites of action [3, 4, 15]. 

However, Clog P and, more generally, Hpophilidty descriptors referring to octanol-water are not the only lipophilicity parameters to be taken into account As mentioned above, isotropic and anisotropic Hpophilidty values gave rise to two different Hpophilidty scales for ionized compounds and thus it is recommended to test both of them (after checking the absence of any coHnearity) when looking for a QSAR model involving ions. 

Lipophilicity and the Control of Undesired Human Ether-a-go-go-related Gene (hERC) Activity 

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. 

are indebted to the University of Turin for financial support. We also thank Pharma Algorithm (http //www.ap-algorithms.com) for the complimentary copy of the ADME Boxes software (version 3.5, release date November 2006). 

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