Atom lipophilicity contributions

Lipophilicity descriptors, in particular, the atomic lipophilicity contribution La in Ghose and Crippen s system, taking into account the environment of an atom, and group lipophilicity Lg defined as a sum of contributions for a non-hydrogen atom and attached hydrogens. 

This led to the concept of fragmentation of the total molecular surface area in combination with multivariate analysis (Stenberg et al. 2001) towards predictive models of drug permeability for more complex datasets. Permeability models were established based on so-called partitioned total surface area (PTSA) descriptors. Each of the PTSA descriptors corresponds to the surface of a certain atom type, differentiated by hybridisation, which results in individual descriptors for e.g. sp3, sp2, and sp carbon atoms. The resulting permeability model based on 19 descriptors finally consisted of oxygen, nitrogen and polar hydrogen surfaces, while the main contribution for prediction of Caco-2 permeability was attributed to PSA. In addition some more lipophilic contributions... 

The Broto-Moreau-Vandicke contribution method is based on hydrophobic atomic constants a measuring the lipophilic contributions of atoms, each described by its nature, neighbouring atoms and associated connectivities, thus implicitly considering some proximity effects and interactions in conjugated systems [Broto etal, 1984b]. Hydrogen atoms and correction factors are not explicitly considered. The model is defined as ... 

Viswanadhan VN, Ghose AK, Wendoloski JJ. Estimating aqueous solvation and lipophilicity of small organic molecules A comparative overview of atom/group contribution methods. Perspect Drug Discov Des 2000 19 85-98. 

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... 

The Meylan-Howard hydrophobic model is derived from an atom/fragment contribution method providing 150 hydrophobic atomic and fragmental constants fi measuring the lipophilic contributions of atoms and fragments in the molecule, together with 250 correction factors [Meylan and Howard, 1995,1996, 2000 KOWWIN - Syracuse Research Corporation, 2008]. 

Figures Log P of homologous alcohols as a function of n (number of alkyl carbon atoms) (a) n-octanol/water, slope 0.54 (lipophilicity contribution of the methylene group) (b) chloro-form/water, slope 0.62 (c) cyclohexane/water, slope 0.65 (reproduced from Figure 11 of ref. [173] with permission from Pergamon Press Ltd., Headington Hill Hall, Oxford 0X3 OBW, UK).

A modified version of the Rekker method, which has to be further evaluated, was recently published [56]. Some other atom-, bond- and group-based calculation procedures e.g. [264—271]) have been developed most of them are reviewed and critically commented in ref. [173]. The calculation of hydrophobic fields from lipophilicity contributions is discussed in chapter 9.2. 

Atom-based lipophilicity contributions and molar refractivity contributions have been derived for 3D QSAR studies [266 — 269]. Audry et ai defined molecular lipophilicity potentials [914—916] for the determination of lipophilic and hydrophilic regions of a molecule. 

Generally, it was stated that the most significant correlation was found between the values of Pmw and po lipophilic parameters and logPRowwin calculated from atom/fragmental contribution values. MlogP correlates with the above-mentioned lipophilic parameters slightly worse than logPRowwin does (r > 0.90). It was found that... 

A volume-related term (expressed by polarizability) and electrostatics (expressed by partial atomic charge) made minor contributions to intestinal absorption in humans. Lipophilicity, expressed by logP or logD values, shows no correlation with the human absorphon data. Recently, similar results were obtained for 154 passively transported drugs on the basis of surface thermodynamics descriptors [39] ... 

Eqn. 8.3 indicates that the binding of nicotinates to the catalytic site of carboxylesterase depends first and mainly on substituent bulk (optimal MR = 35, which corresponds to a quite large substituent such as heptyl or 2-phenoxyethyl). In addition, affinity increases with increasing lipophilicity. The influence of A S appears complex and difficult to interpret, perhaps suggesting that the interaction of the carbonyl C-atom with the catalytic OH group contributes to affinity. 

Atom-based Methods As for fragmental methods, the molecule is considered as composed of fragments, but these latter are single atoms instead of functional groups. Each atom is characterized by its own lipophilicity constant and the global lipophilicity is then a sum of each contribution (Equation 5.4). 

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