Log P calculation

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. 

Break down the chemical structure into fragments that are present in the fragment table. 

Add together the fragment values and apply the necessary correction factors to obtain a calculated log P. 

In these two examples, the knowledge base or rule base of the expert system consists of the fragment values and correction factors, along with any associated rules for breaking down a compound into appropriate fragments. Although the numerical values for the fragments and factors have been derived from experimental data (log P measurements) it has 

1 TIMESTAMP 1 LOCAL NAME 5 LOOP 1 LOGPSTAR 1 CLOGP 1 CMR 1 MOLFORM 1 PKA 

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Thus, a list of 1 5 descriptors was calculated for these purposes, as described below. The partition coefficient log P (calculated by a method based on the Gho.sc/Crip-pen approach [11]) (see also Chapter X, Section 1.1 in the Handbook) was calculated because it affects the solubility dramatically [17, 18]. All the other descriptors were calculated with the program PETRA (Parameter Estimation for the Treatment of Reactivity Applications) [28. ... 

Fig. 1.7 Correlation between virtual log P (calculated with the molecular lipophilicity potential) and the dipole moment (f = 0.76) as obtained from MD simulation of acetylcholine in water. Reproduced from Ref [16] with kind permission of American Chemical Society 2005.

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. 

Regression analyses revealed systematic differences between experimental log P and log P calculations based on the summation of fragment values. These differences could be attributed to chemical characteristics of the molecules, which in turn allowed the definition of correction rules such as chain conjugation, electronegativity facing bulk or the proximity effect, which describes the presence of electronegative centers in a molecule separated by one or two carbons. Correction values needed for log P calculation were shown to represent multiples of a constant value of 0.289, which is known as the magic constant (CM). 

The actual 2/ system [34] lists 13 correction rules and 169 fragment values, including 14 new heterocyclic fragments as well as doubly and triply halogenated methyls. A typical calculation is depicted in Fig. 14.1 for quinidine. The 2/system is the only fragment method allowing manual log P calculation. Computerized... 

Log P calculation for quinidine with the atom contribution method according to Ghose and Crippen. R group connected to C X heteroatom = double bond aromatic bond aromatic single bond (e.g. C=N in pyrrole) subscripts give the hybridization state and superscripts the formal oxidization number. For the quinidine structure see Fig. 14.1. 

Klopman, G., U,). W., Wang, S., Dimayuga, M. Computer automated log P calculations based on an extended group contribution approach. 

Use of Solvatochromic Equations Solvatochromic analysis for log P calculations appears to be one of the more useful approach built using linear free energy relationship (LEER) described by the general Equation (5.6) [58] ... 

Klopman, G., et al., Computer Automated Log P Calculation Based on an Extended Group Contribution Approach. J. Chem. Inf. Comput. Sci., 1994 34, 752-781. 

Most suppliers of log P calculating software (see van de Waterbeemd, 1996) present a statistical evaluation of their program s performance. This usually is based on regression of calculated versus measured values and an examination of the regression coefficient and standard deviation. 

Structure A is the one depicted in Merck and the one stored in the ACD dictionary but labeled as minor form when a log P calculation is made. The ACD/LogP calculations for A and B are +1.55 and +2.04, respectively. Two measured values have been reported, 1.74 and 1.85. KOWWIN and CLOGP calculate structure B very nearly the same (1.29 and 1.22), but both see structure A as considerably more hydrophilic (-0.15 and +0.60). 

The bottom line is that a prospective user should spend sufficient time with an adequate demonstration version of any computerized log P calculator, including the many not directly mentioned in this chapter, to make sure it will perform to meet his/her specific needs. Perhaps the best way a prospect can shop for vendors supplying such programs is through the contacts van de Waterbeemd lists (1996) or http / /www.pharma.ethz.ch/ qsar/logp.html. 

Klopman, G., J.-Y. Li, S. Wang, and M. Dimayuga. 1994. Computer Automated log P Calculations Based on an Extended Group Contribution Approach. J. Chem. Inf. Comput. Sci. 34, 752-781. Klopman, G., and S. Wang. 1991. A Computer Automated Structure Evaluation (CASE) Approach to Calculation of Partition Coefficients. J. Comput. Chem. 8 1025-1034. 

Leo, A.J. 1995a. The Future of log P Calculation. In Lipophilicity in Drug Action and Toxicology, V. 

Leo, A.J. 1995b. Critique of Recent Comparison of Log P Calculation Methods. Chem. Pharm. Bull. 

The latest versions of the DfW software incorporate a reasoning engine that uses log P (calculated by a C log P plug-in) and molecular mass to predict the likelihood that a chemical will express its potential toxicity regarding a specific endpoint in the selected species. This feature is, for example, used in the... 

Many models for log P prediction have been developed and published in the literature, which is a consequence of the availability of a large amount of log P data. There are much fewer log D models and, moreover, models built with large datasets are almost exclusively from large companies.One can distinguish two main groups for log P calculation fragmental and based on descriptors calculated for the whole molecule. ... 

Recent attempts to compute log P calculations have resulted in the development of sol-vatochromic parameters (151, 152). This approach was proposed by Kamlet et al. and focused on molecular properties. In its simplest form it can be expressed as follows ... 

For lipophilicity assessment, calibration equations with types similar to Eqs. 3 and 4 should be constructed using compounds with known log P values. These calibration equations are applied for further log P calculations. According to the author, it is recommended to measure more than one set of isocratic Rm or log k values to construct the corresponding calibration equations and to calculate the average log... 

The most popular approaches to log P calculation are listed below. 

Another model was proposed based on atomic composition of the molecule only, ignoring the infiuence ofthe charge density descriptors on the log P calculation [Klopman, Namboodiri et al, 1985]. The best-fitted proposed model is... 

These are hydrophobic atomic constants a measuring the lipophilic contribution of atoms in the molecule, each described by its neighboring atoms [Ghose and Crippen, 1986 Ghose, Pritchett et al, 1988 Viswanadhan, Ghose et al, 1989]. The model for log P calculation is defined as... 

This is a model for log P calculation based on a group-contribution method proposed by Wang Remdao et al. [Wang, Fu et al, 1997 Wang, Gao et al, 2000]. The model is defined in terms of the solvent accessible surface area and the atomic charges of 76 atom-types, together with five additional correction factors, as... 

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