Nys and Rekker

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). 

Doucette and Andren [4] have compared six methods to estimate Kow for highly hydrophobic aromatic compounds such as halogenated benzenes, biphenyls, diben-zofurans, and dibenzo-p-dioxins with log Kow values ranging from 2.13 to 8.58. The comparison includes the GCM of Hansch and Leo, the GCM of Nys and Rekker, and correlations based on the following molecular descriptors HPLC retention times, M, TSA, and MCIs. The method using MCIs had the smallest average percent error. The method is... 

Method of Nys and Rekker The Nys and Rekker method [53,54] has been developed for mono- and di-substituted benzenes. The substituents considered are halogen atoms and hydroxyl, ether, amino, nitro, and carboxyl groups, for which contributions have been calculated by multiple regression analysis (s = 0.106, r = 0.994, F = 1405). Rekker discusses the extension of his approach to other compound classes, such as PAHs, pyridines, quinolines, and isoquinolines. 

Nys and Rekker (Nys, 1973) were the first to publish a method of calculating log Poctby the addition of fragment values, and this procedure has been improved over time (Rekker, 1992). The designers determine what constitutes a valid fragment and verify the selection using a large database of measured values. 

Also simply called hydrophobic fragmental constants, these are measures of the absolute lipophilicity contribution of specific molecular fragments to the lipophilicity of the molecule [Nys and Rekker, 1973 Nys and Rekker, 1974 Rekker, 1 7a Rekker, 1977b Rekker and De Kort, 1979]. 

Although n values are useful for datasets that contain analogs of a parent structure, it is also of interest to develop QSARs with sets of more diverse structures. In the early 1970s, Nys and Rekker showed that to calculate an... 

The log C n-octanol/water partition coefficients (log P) for compounds selected for this study were obtained from those reported by Hansch et. (25), or were calculated from fragmental-constants as reported by Nys and Rekker (26). The Taft Steric (E ) and polar (o- ) constants were obtained from those values reported by Taft (27). 

One of the earliest applications of expert systems in the field of QSAR was the development of calculation schemes for octanol/water partition coefficients. Although the early work with n constants had shown that they were more or less additive, a number of anomalies had been identified. In addition, in order to calculate log P values from n constants it is necessary to have a measured log P for the parent and this, of course, is often unavailable. One approach to the question of how to calculate log P from chemical structure is to analyse a large number of measured log P values so as to determine the average contribution of particular chemical fragments (Nys and Rekker 1973). The fragment contributions constitute the rules of the expert system, extra rules being supplied in the form of correction factors. Operation of this expert system consists of the following few simple steps. 

Nys and Rekker were the first to publish a method of calculating log Poet from scratch by the addition of values characteristic of structural fragments. This method was elucidated further by Rekker and by Rekker and Mannhold, and has been used widely, both as a manual method and by computer as PrologP and SanalogP. 

Nys, G.G. and Rekker, R.F. (1973). Statistical Analysis of a Series of Partition Coefficients with Special Reference to the Predictability of Folding of Drug Molecules. The Introduction of Hydrophobic Fragmental Constants ((Values). Eur.I.Med.Chem.,8,521-535. 

Nys, G. G. and Rekker, R. F. (1973) Statistical analysis of a series of partition coefficients with special reference to the predictability of folding drug molecules. The introduction of hydrophobic fragmental constant (f values). Chim. Ther., 5, 521-35. 

Nys, G. G., Rekker, R. F. The concept of hydrophobic fragmental constants (f values). 11. Extension of its applicability to the calculation of lipophilidties of aromatic and hetero-aromatic structures. Chim. Therap. 1974, 9, 361-375. 

Calculation of log P based on revised Nys-Rekker fragmental constants is provided by some software, such as PROLOG and SANALOGP. 

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