Lipophilicity calculation from molecular

Lipophilicity in particular, as reflected in partition coefficients between aqueous and non-aqueous media most commonly water (or aqueous buffer) and Z-octanol,has received much attention [105,141,152,153,176,199,232,233]. Logic )W for the octanol-water system has been shown to be approximately additive and constitutive, and hence, schemes for its a priori calculation from molecular structure have been devised using either substituent tt values or substructural fragment constants [289, 299]. The approximate nature of any partition coefficient has been frequently emphasized and, indeed, some of the structural features that cause unreliability have been identified and accommodated. Other complications such as steric effects, conformational effects, and substitution at the active positions of hetero-aromatic rings have been observed but cannot as yet be accounted for completely and systematically. Theoretical statistical and topological methods to approach some of these problems have been reported [116-119,175,289,300]. The observations of linear relationships among partition coefficients between water and various organic solvents have been extended and qualified to include other dose-response relationships [120-122,160,161,299-302]. 

Gaillard, P. Carrupt, P.-A. Testa, B., The conformation-dependent lipophilicity of morphine glucuronides as calculated from the molecular lipophilicity potential, Bioorg. Med. Chem. Lett. 4, 737-742 (1994). 

A modification of the atomic approach was also proposed by Gaillard et al. using molecular lipophilicity potential (MLP) as a 3D source of two lipophilicity parameters calculated from the water-accessible surface, namely a hydrophobic parameter expressed as the sum ofthe positive lipophilicity potential (EM LP+) and a polar parameter expressed as the sum of the negative lipophilicity potential (EMLP—)... 

Other measures of properties in 3D, such as Molecular Lipophilicity Potential (MLPot) and Molecular Hydrogen Bond Potential (MHBP), have been used to characterize 3D properties. They are defined for points on a molecular surface created around the molecule and calculated from the summation of contributions from the substructural fragments making up the molecule weighted by the distance function. The hydrogen bond potentials include an angle-dependent function. 

Gaillard, R, Carrupt, P.-A. and Testa, B. (1994a). The Conformation-Dependent Lipophilicity of Morphine Glucuronides as Calculated from their Molecular Lipophilicity Potential. Bioorg. Med.Chem.Lett., 4,737-742. 

Skin-snake-model percutaneous absorption Relationships between the in vitro permeability of basic compounds through shed-snake skin as a suitable model membrane for human stratum corneum and their physio-chemical properties were investigated. Compounds with low pKa values were selected to compare the permeabilities of the nonionized forms of the compounds. Steady-state penetration was achieved immediately without a lag time for all compounds. Flux rate and permeability coefficient were calculated from the steady-state penetration data and relationships between these parameters and the physico-chemical properties were investigated. The results showed that permeability may be controlled by the lipophilicity and the molecular size of the compounds. Equations were developed to predict the permeability from the MWs and the partition coefficients of basic compounds. 

Thus, the detection of the direct and selective influence of the paramagnetic lipophilic electron relay on the H-NMR spectra of the surrounding lipid molecules, which constitute the bilayer lipid membranes, appears to be direct evidence for the localization of the paramagnetic moiety of lipophilic cetylviologen cation radicals just near the surface of the vesicle membrane. Evidently, this coincides with the above data from molecular mechanics calculations. 

Research into optimal formulations is based on the idea of cohesive energy ratio (CER). This was originally developed to stabilise classic non-ionic surfactant emulsions [6.13]. Despite its limitations, the CER concept unifies the ideas of solubility parameters and HUB. Recall that the HLB is a measure of the emulsifying power of surfactants and is based on their hydrophile-lipophile balance [6.3]. It can be calculated from a simple formula involving only relative weights of sequences HLB = 20 x Mh/Mt, where Mh is the molecular weight... 

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.

Using molecular mechanics calculations to assess the three-dimensional shape of a molecule, various surface properties such as polarity and size can be calculated. The dynamic molecular surface properties can be determined from the (low energy) conformation(s) of the drug molecule obtained by molecular mechanics calculations of conformational preferences. The potential advantage of this method is that the calculated surface character-sitics determine numerous physicochemical properties of the molecules including lipophilicity, the energy of hydration and the hydrogen bond formation capacity [187-... 

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