Examples of Applications in Drug Design

Lipophilicity is undoubtedly the most important physicochemical property used in drug design and QSAR studies. Besides numerous experimental parameters, calculated lipophilicity properties play an important role in QSAR and drug design, as illustrated by the large number of publications devoted to such applications. Because it is impossible here to provide an exhaustive overview of these applications, we focus our attention on a few examples, giving a flavor of what can be performed with computed lipophilicity properties. 

A number of literature examples have demonstrated interest in comparing experimental and computed lipophilicity parameters - to reveal intramolecular interactions of significance in interpreting the pharmacokinetic behavior of drugs. 

a comparison between HPLC-derived lipophilicity indices and calculated log P values for a series of 8-substituted xanthines showed a clear influence of conformational effects. 8 In this case, Rekker s method was unable to take 3D effects into account, but the difference between experimental and predicted values was structure dependent rather than constant. Conformational analyses confirmed that a smaller than predicted lipophilicity was associated with folded conformers stabilized by hydrophobic and van der Waals forces and having part of their nonpolar surface masked from the aqueous phase. A 4D theoretical approach (log P calculations by MLP for conformers generated by high temperature molecular dynamics) suggests that these effects should be lower in an w-octanol/water system than in RP-HPLC. Indeed, the n-octanol/water system is not the most suitable model to study intramolecular interactions in nonpolar media because a surprisingly high proportion of water is dissolved in the w-octanol. Recall, however, that w-octanol, despite some limitations, was selected by many workers in the field as a model for biological membranes. 

Interest in comparing several predicted partition coefficients to detect intramolecular effects in nucleosides is illustrated by the work of Viswanadhan 

The distribution of the two morphine glucuronides, morphine-3-O-p-D-glucuronide (M3G) and morphine-6-O-p-D-glucuronide has been 

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