The Molecule in the Background

While molecular pharmacology deals with the. response of a cell to a substance recognized as a message, medicinal chemistry attempts to unveil the semantics, and perhaps also the syntax, of the molecular language which encodes these messages. In order to achieve this, molecular structure has to be described in a pharmacologically relevant way; adoption of a multilevel description of molecular structure [12] appears to be the best approach to this end. Such a description starts at a simple geometrical level, continues with a stereoelectronic one, and ends up at levels of intermolecular interactions. It is at these latter levels that one encounters properties like solubility and lipophilicity whose high content in structural information remains difficult to understand fully.

Lipophilicity, however, is far from being only an empirical tool in structure-activity analysis. It is also a unique probe that can be used to unravel the complex and dynamic interplay between intermolecular forces and intramolecular interactions in solutes of interest. The former comprise interactions between a solute and the aqueous and organic phases, namely [1, 2, 13]:

• Ion-ion and ion-dipole (permanent, induced) interactions (for ionic solutes);

• Charge transfer interactions;

• Hydrogen bonds (normal, reinforced);

• Van der Waals interactions (forces of orientation, induction, and dispersion);

• Hydrophobic bonds.

Intramolecular interactions that influence lipophilicity can be classified as follows:

• Through-bond electronic effects a) in aromatic systems, and b) across aliphatic segments;

• Through-space electronic/polar effects comprising a) internal electrostatic bonds (ionic bonds, H-bonds, and other electrostatic bonds), b) internal electrostatic repulsion, and c) collision of hydration spheres due to proximity effects between polar groups;

• Through-space steric/hydrophobic effects comprising a) internal hydrophobic bonds (hydrophobic collapse), and b) internal steric hindrance.

Intramolecular interactions can explain differences in lipophilicity seen between re-gioisomers and between configurational diastereomers. The interplay between conformational diastereomerism and lipophilicity, which is particularly manifest in molecular chameleons, is gaining increasing recognition in compounds of sufficient size and functional complexity [14]. Furthermore, intramolecular interactions affecting lipophilicity represent a major and incompletely understood challenge to the accuracy of current fragmental systems.

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