Interactions Encoded in Lipophilicity

Functional groups in solute molecules interact with each other in a number of ways depending on their own electronic and steric properties, on the number and nature of interconnecting bonds, and on intramolecular distances. Schematically, a number of dichotomous distinctions can be made (e.g., electronic vs. steric effects, through-bond vs. through-space interactions). Such distinctions may be misleading, however, because they tend to neglect overlaps of effects and intermediate cases.  

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Testa, B. Carrupt, P.-A. Gaillard, P. Tsai, R.-S. Intramolecular Interactions Encoded in Lipophilicity ... 

Testa, B. Carrupt, P.-A. Gaillard, P. Tsai, R.-S. Intramolecular interactions encoded in lipophilicity their nature and significance. In Lipophilicity in Drug Action and Toxicology, Pliska, V., Testa, B., van de Waterbeemd, H., Eds. VCH Weinheim, 1996 49 71. 

Such an expression allows comparison of molecular recognition forces with the interactions encoded in lipophilicity. This is done in Figure 1, where the polar component of lipophilicity is seen to correspond to ion—dipole bonds, hydrogen bonds, orientation forces, and induction forces, whereas the hydrophobic component corresponds to dispersion forces and hydrophobic interactions. Only a limited number of recognition forces cannot find expression in lipophilicity as conventionally measured, namely, ionic bonds, charge transfer interactions, and aryl/aryl stacking interactions. ... 

Based on the explicit treatment of the most important intermolecular interactions (i.e., steric and electrostatic), 3D-QSAR techniques have flourished in the field of ligand—receptor interactions.Because of the interconnection between recognition forces and intermolecular interactions encoded in lipophilicity (Figure 1), the benefits of these techniques in the prediction of partition coefficients from the 3D structure were explored. 

B. Testa, P.-A. Carrupt, P. Gaillard, and R. S. Tsai, in Upophilicity in Drug Research, V. Pliska, B. Testa, and H. van de Waterbeemd, Eds., VCH Publishers, Weinheim, 1996, pp. 49-71. Intramolecular Interactions Encoded in Lipophilicity Their Nature and Significance. 

Because many intramolecular interactions are encoded in lipophilicity, the calculation of log F values becomes a powerful tool to understand molecular structure. Here, the latest development—and one that is discussed at length later—is an integrated approach to the fbur dimensional structure of com-... 

A proper understanding of these methods calls for a description of the structural information encoded in lipophilicity that is, the intermolecular forces and the intramolecular interactions it expresses. These aspects are presented in the next three sections. Further sections discuss the computational methods used to calculate and understand lipophilicity. Selected applications of the computational methods conclude the chapter. 

Electric polarization, dipole moments and other related physical quantities, such as multipole moments and polarizabilities, constitute another group of both local and molecular descriptors, which can be defined either in terms of classical physics or quantum mechanics. They encode information about the charge distribution in molecules [Bbttcher et al, 1973]. They are particularly important in modelling solvation properties of compounds which depend on solute/solvent interactions and in fact are frequently used to represent the -> dipolarity/polarizability term in - linear solvation energy relationships. Moreover, they can be used to model the polar interactions which contribute to the determination of the -> lipophilicity of compounds. 

The steric term used in factorizing lipophilicity can be defined as a descriptor of the solute s capacity to enter nonpolar interactions with the aqueous and organic phases (i.e., hydrophobic interactions and dispersion forces). Whether cavity formation also plays a role is debatable and will not be discussed here. To simplify the vocabulary in this chapter, it is convenient to equate hydrophobicity with the nonpolar interactions encoded by the steric term. In this nomenclature, hydrophobidty is not synonymous with lipophilicity, but a mere component of it. 

The complexity of the structural parameters in this model illustrates the broad information content of lipophilicity, as discussed above. Indeed, the dominant descriptors (CX) - and (NO) - account for hydrophobic and hydrophilic contributions, respectively, whereas specific parameters encode intramolecular interactions. Note that the number of structural parameters needed to obtain good structure-log P relationships can be reduced in smaller and simpler series of solutes compared to the original set of 1230 solutes. An example of a log P calculation is shown in Figure 6. 

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