Setting the Scene

At the end of the 7th QSAR Symposium held in Interlaken in 1988, the organisers asked a number of participants which topics they felt should require greater attention in future meetings. The list of suggestions was indeed long and diverse. One subject, however, was mentioned almost unanimously, namely the pharmacological, toxicolog-ical, and pharmacokinetic significance of weak interactions in general and lipophilicity in particular.

This interest is understandable and legitimate. Weak interactions such as hydrogen bonds, van der Waals forces, hydrophobic effects, and charge transfer interactions are absolutely essential for molecular recognition and interactions in living systems. They underlie the formation of firmly determined molecular and supramolecular structures (for instance in biological macromolecules, membranes, etc.) and, at the same time, enable their amazing flexibility and adaptability. As a rule, several weak forces participate in any interaction occurring in a biological system. Due to their superposition, intermolecular and intramolecular complexes may exhibit a broad range of association constants from about 104 mol L"1 (enzyme-substrate complexes) to 1014 mol L"1 (polyvalent antibody-antigen complexes). Since biologically important macromolecules always contain a variety of polar and nonpolar sites, the role of polar and hydrophobic forces is of utmost significance in all processes of biological recognition.

Before going any further, it appears appropriate to comment on the words "hydro-phobicity" and "lipophilicity" since they are used rather loosely and inconsistently in the literature. As discussed in greater details below, lipophilicity is a molecular property expressing the relative affinity of solutes for an aqueous phase and an organic, water-immiscible solvent. As such, lipophilicity encodes most of the intermolecular forces that can take place between a solute and a solvent. In contrast, hydrophobicity is a consequence of attractive forces between nonpolar groups (e.g., hydrocarbon chains and rings) and therefore is but one component of lipophilicity. Factorization of lipophilicity into its polar and hydrophobic components contributes considerably to our understanding of the nature of lipophilicity and its role in the biological world [1, 2].

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