Outlook Molecular Polymorphism in Drug Design

A discussion of intermolecular forces encoded in lipophilicity (section 4.2), intramolecular interactions influencing lipophilicity (section 4.3), and structural factors influencing intramolecular interactions (section 4.4) shows very clearly their intercon-nectedness and interdependence. A schematic representation of these relation is proposed in Fig. 9, which can be simplified as follows:

Table 4. Major intramolecular and intermolecular processes underlying molecular polymorphism

Intramolecular processes (formally) Intermolecular processes

• Valence isomerization

• Tautomerism

• Inversion of configuration

• Conformational behavior

• Internal hydrophobic bonds and hydrophobic collapse

• Internal electrostatic bonds and hydrophilic collapse

Prototropic equilibria (acid-base behavior) Hydration and solvation Self-association

Binding to macromolecules and consequences thereof

• solubility and partitioning properties are first a function of intermolecular forces;

• intermolecular forces and intramolecular interactions influence each other in an intimate and undissociable way;

• in addition,intermolecular forces and intramolecular interactions depend on, and influence in return, such molecular properties as conformation, electronic distribution and ionization.

Figure 9 brings us back to the multilevel description of molecular structure and properties discussed in section 4.1. It emphasizes the holistic character of molecular structure and properties, which should most fruitfully be approached in the global perspective of molecular polymorphism (Table 4). Only in this way can we hope to progress in our conceptual understanding of molecular structure and in describing it with improved depth and sophistication.

Acknowledgements

The authors are indebted to the Swiss National Science Foundation for financial support.

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Lipophilicity in Drug Action and Toxicology edited by Vladimir PliSka,Bernard Testa & Han van de Waterbeemd Copyright© VCH Verlagsgesellschaft mbH,1996

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