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The predictive power of four calculation procedures for molecular lipophilicity is checked by comparing with experimental data (log Pand chromatographical RMw) taken from the literature. Two sets of test compounds are used: the first comprises simple organic molecules and the second consists of more complicated drug molecules. Our comparative evaluation leads us to conclude that the predictive power is significantly better for not too complicated organic molecules than for drugs with complicated structural pattern. The four investigated calculation procedures should be arranged in two groups with significantly differing predictive power: (a) Rekker and Hansch/Leo and (b) Ghose/Crippen and Suzuki/Kudo. This conclusion is based on a statistical control using log Pand RMwas the independent parameters. Correlations have in common: (1) slopes in correlations with calculated data based on fragmental methods are not significantly different from 1; calculations with data from atom-based procedures show up in most cases with slopes below 1. (2) The accompanying overall statistics underline the superiority of the fragmental methods. We think that all four tested calculation procedures have their own restrictions; for future development we would advise a thorough reconsideration of structural effects not fully (or even not at all) incorporated in the data sets. Special attention will have to be paid to the conformational aspects of lipophilic behavior.

Two experimental (log P, RMw) and 17 calculation descriptors for molecular lipophilicity (fragmental, atom-based or based on molecular properties) were investigated by multivariate analysis for a database of 159 compounds including both simple structures as well as more complex drug molecules. Principal component analysis (PCA) of the entire database exhibits a clustering of chemical groups; preciseness of clustering corresponds to chemical similarity. Thus, diversity searching in databases might effectively be performed by PCA on the basis of calculated log P. The comparative validity check of experimental and computational procedures by regression analysis and PCA was performed with a chemically balanced, reduced data set (n=55) representing 11 chemical groups with 5 members each. Regression of experimental descriptors (log Poct versus RMw) proves that chromatographic data, obtained under well-defined experimental conditions, can be used as valid substitutes for log P. Regression of calculated versus experimental lipophilicity data shows a superiority of fragmental over atom-based methods and approaches based on molecular properties, as indicated by correlation coefficients, slopes and intercepts. In addition, PCA revealed that fragmental methods (Rekker-type, KOWWIN, KLOGP) sense the compound ranking in log P data to almost the same extent as experimental approaches. For atom-based procedures and CLOGP, both the comparability of absolute values and the sensing of the compound ranking in the database are slightly less. This trend is more pronounced for the methods based on molecular properties, with the exception of BLOGP.

In the first part of this paper we briefly describe experimental approaches to quantifying molecular lipophilicity by reversed-phase thin-layer chromatography (RP-TLC) and reversed-phase high performance liquid chromatography (RP-HPLC). The central part is devoted to representative cases of RP-TLC and RP-HPLC investigations of both simple organic structures and more complex drug molecules. Conditions for a valid comparability of these chromatographic data with log P are discussed.

A hydrophobic fragmental system was developed for application in the study of aliphatic hydrocarbon/water (ahc/w) partitioning. The final version presented here is based on an optimized coupling of the ahc/w-system with f-constants for octanol/water partitioning. A total of 70 f-values are now available in the aliphatic hydrocarbon/water system. The aliphatic hydrocarbon/water system appears to be especially useful in the evaluation of log Poct data for compounds with comparatively high lipophilicity. As a first, preliminary validity check the new system is applied to pharmaco-chemical studies on penetration of blood-brain barrier by drugs and simple organic compounds.

In the first part of this paper we briefly describe experimental (octanol/water partitioning) as well as computational approaches to quantifying molecular lipophilicity. The central section focuses on the hydrophobic fragmental constant approach (Σf-system) as developed by Rekker and his group, starting in the early seventies. The original approach has been extended and revised a number of times; the most recent updating is presented here. It is followed by a detailed description of how to apply the correction factor CM. The practical procedure of Σf-calculations is described for some examples and the validity of these calculations is verified by comparison with other calculation methods and experimental data.

In the first part of this paper we briefly describe experimental approaches to quantifying molecular lipophilicity by reversed-phase thin-layer chromatography (RP-TLC) and reversed-phase high performance liquid chromatography (RP-HPLC). The central part is devoted to representative cases of RP-TLC and RP-HPLC investigations of both simple organic structures and more complex drug molecules. Conditions for a valid comparability of these chromatographic data with log P are discussed.

A hydrophobic fragmental system was developed for application in the study of aliphatic hydrocarbon/water (ahc/w) partitioning. The final version presented here is based on an optimized coupling of the ahc/w-system with f-constants for octanol/water partitioning. A total of 70 f-values are now available in the aliphatic hydrocarbon/water system. The aliphatic hydrocarbon/water system appears to be especially useful in the evaluation of log Poct data for compounds with comparatively high lipophilicity. As a first, preliminary validity check the new system is applied to pharmaco-chemical studies on penetration of blood-brain barrier by drugs and simple organic compounds.

In the first part of this paper we briefly describe experimental (octanol/water partitioning) as well as computational approaches to quantifying molecular lipophilicity. The central section focuses on the hydrophobic fragmental constant approach (Σf-system) as developed by Rekker and his group, starting in the early seventies. The original approach has been extended and revised a number of times; the most recent updating is presented here. It is followed by a detailed description of how to apply the correction factor CM. The practical procedure of Σf-calculations is described for some examples and the validity of these calculations is verified by comparison with other calculation methods and experimental data.

In the first part of this paper we briefly describe experimental approaches to quantifying molecular lipophilicity by reversed-phase thin-layer chromatography (RP-TLC) and reversed-phase high performance liquid chromatography (RP-HPLC). The central part is devoted to representative cases of RP-TLC and RP-HPLC investigations of both simple organic structures and more complex drug molecules. Conditions for a valid comparability of these chromatographic data with log P are discussed.

A hydrophobic fragmental system was developed for application in the study of aliphatic hydrocarbon/water (ahc/w) partitioning. The final version presented here is based on an optimized coupling of the ahc/w-system with f-constants for octanol/water partitioning. A total of 70 f-values are now available in the aliphatic hydrocarbon/water system. The aliphatic hydrocarbon/water system appears to be especially useful in the evaluation of log Poct data for compounds with comparatively high lipophilicity. As a first, preliminary validity check the new system is applied to pharmaco-chemical studies on penetration of blood-brain barrier by drugs and simple organic compounds.

In the first part of this paper we briefly describe experimental (octanol/water partitioning) as well as computational approaches to quantifying molecular lipophilicity. The central section focuses on the hydrophobic fragmental constant approach (Σf-system) as developed by Rekker and his group, starting in the early seventies. The original approach has been extended and revised a number of times; the most recent updating is presented here. It is followed by a detailed description of how to apply the correction factor CM. The practical procedure of Σf-calculations is described for some examples and the validity of these calculations is verified by comparison with other calculation methods and experimental data.

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