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Substructure and whole molecule approaches for calculating log P

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Abstract

Lipophilicity is a major determinant of pharmacokinetic and pharmacodynamic properties of drug molecules. Correspondingly, there is great interest in medicinal chemistry in developing methods of deriving the quantitative descriptor of lipophilicity, the partition coefficient P, from molecular structure. Roughly, methods for calculating log P can be divided into two major classes:

• Substructure approaches have in common that molecules are cut into atoms (atom contribution methods) or groups (fragmental methods); summing the single-atom or fragmental contributions (supplemented by applying correction rules in the latter case) results in the final log P.

• Whole molecule approaches inspect the entire molecule; they use for instance molecular lipophilicity potentials (MLP), topological indices or molecular properties to quantify log P.

In this review, representative members of substructure and whole molecule approaches for calculating log P are described; their advantages and shortcomings are discussed. Finally, the predictive power of some calculation methods is compared and a scheme for classifying calculation methods is proposed.

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  1. Molecular Drug Research Group, Building 22.03, Heinrich-Heine-Universität, Universitätsstraße 1, 40225, Düsseldorf, Germany

    Raimund Mannhold

  2. Department of Drug Metabolism, Pfizer Central Research, Sandwich, Kent, CT13 9NJ, UK

    Han van de Waterbeemd

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Mannhold, R., van de Waterbeemd, H. Substructure and whole molecule approaches for calculating log P. J Comput Aided Mol Des 15, 337–354 (2001). https://doi.org/10.1023/A:1011107422318

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