Fragment constant approach

The obvious drawback of this method is that the parent solute, at least, has to be available or must be synthesized, and its log P value has to be determined experimentally. Nys and Rekker therefore developed a method known as the fragmental constant approach, which is based on the additivity of fragment contributions to the molecular lipophilidty [7] (see Eq. (9), where a( is the inddence of fragment i, fi the lipophilic fragment constant, Ci a corredion factor, and the frequency of Cm). 

With only few exceptions, most log P programs refer to the octanol-water system. Based on Rekker s fragmental constant approach, a log P calculation for aliphatic hydrocarbon-water partitioning has been reported [96]. Another more recent approach to alkane-water log P and log D is based on the program VolSurf [97]. It is believed that these values may offer a better predictor for uptake in the brain. 

Mannhold, R., Rekker, R. F. The hydrophobic fragmental constant approach for calculating log P in octanol/ water and aliphatic hydrocarbon/water systems. Perspect. Drug Discov. Des. 2000, 18,1-18. 

Rekker, R. F., Mannhold, R. Calculation of Drug Lipophilicity. The Hydrophobic Fragmental Constant Approach, VCH, Weinheim, 1992. 

The lipophilic behaviour of organic compounds 1. An updating of the hydrophobic fragmental constant approach. Quantitative Structure-Activity Relationships, 17, 517-536. 

Direct calculation of P requires the surface tension and density of the liquid and the density of the vapor. However, tables of measured P values are available, and a fragment constant approach also can be used to estimate P (Quayle, 1953). 

Mannhold, R., Rekker, R.F., Dross, K., Bijloo, G.J. and de Vries, G. (1998b). The Lipophilic Behaviour of Organic Compounds 1. An Updating of the Hydrophobic Fragmental Constant Approach. Quant.Struct.-Act.Relat., 17,517-536. [R]... 

Solution of equations 5-1 and 5-2 requires site-specific values as well as chemical-specific values. Critical chemical-specific properties in the above equations are the Henry s law constant (H), the organic carbon/water partition coefficient (Koc), and the effective diffusion coefficient through soil (Deff). Henry s law constants are estimated using solubility and vapor pressure values obtained from data compilations. The Koc is estimated from the octanol-water coefficient (Kow) and is commonly estimated from the Hansch and Leo (1979) fragment constant approach (TPHCWG 1997b) ... 

Related to the above is the intriguing possibility that physical properties can be calculated knowing only molecular structure, completely obviating the need for a sample of the substance or any prior laboratory work with it. For Kqw, the calculation from structure uses the fragment constant approach (13) or early versions of it (12). Briefly, the method employs empiric-... 

Rekker, R.F., and R. Mannhold. 1992. Calculation of Drug Lipophilicity The Hydrophobic Fragmental Constant Approach. Weinheim, Germany VCH. 

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