Calculated lipophilicity potential

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.

The presenee of intramoleeular interaetions ean be eheeked by eomparing calculated and experimental log P values. Sueh identifieation ean yet only be obtained for the water-OCT system, sinee eomputed lipophilieity values have only been derived for this solvent pair. Due to its simplicity and its easy adaptation to eomplex structures, Rekker s calculation method is often appreciated, but more sophistieated approaches like that evaluating log P using the molecular lipophilicity potential (MLP) has also been employed. 

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). 

The derivation of the 3D-LogP descriptor requires a suitable 3D space for the calculation of the molecular lipophilicity potential and validated MLP parameters. 

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. 

Carrupt P-A, Gaillard P, Billois F, Weber P, Testa B, Meyer C, et al. The molecular lipophilicity potential (MLP) A new tool for logP calculations and docking, and in comparative molecular field analysis (CoMFA). In Pliska V, Testa B, van de Waterbeemd H, editors, Lipophilicity in drug action and toxicology. Weinheim VCH, 1996. p. 195-217. 

Often ignored is the fact that log P/D is a conformation-dependent property [161], which has elegantly been demonstrated with the molecular lipophilicity potential (MLP) descriptor [87]. The MLP algorithm allows to calculate virtual log P values in conformational space. 

Plasma area under the concentration—time curves (AUCs) of 57 NCEs were determined following oral cassette administration (5—9 NCEs/cassette) to mice. Physicochemical properties [such as, molecular weight, calculated molar refractivity, and calculated lipophilicity (clogP)] and molecular descriptors [such as presence or absence of N-methylation, cyclobutyl moiety, or heteroatoms (non-C,H,0,N)] were calculated or estimated for these compounds. This structural data, along with the corresponding pharmacokinetic parameters (primarily AUC), were used to develop artificial neural network models [8]. These models were used to predict the AUCs of compounds under synthesis [10]. This approach demonstrates that predictive models could be developed which potentially predict in vivo pharmacokinetics of NCEs under synthesis. Similar examples have been reported elsewhere [11—13]. 

The Molecular Lipophilicity Potential (MLP) describes the combined lipophilic effect of all fragments in a molecule on its environment and can be calculated at any point in space around the molecule [Audry, Dubost et al., 1986, 1992 Fauchere, Quarendon et al, 1988 Furet, Sele et al., 1988 Audry, Dallet et al., 1989]. It is defined by considering a molecule surrounded by nonpolar or low polarity organic solvent molecules, and assuming that the solvent molecule distribution around the considered molecule depends on the fragmental or atomic contributions to log P and the distances at which the solvent molecules are from the target molecule. Therefore, the molecular lipophilicity potential at each feth grid point is calculated as... 

In contrast to other potentials, the lipophilicity potential is not obtained by calculating the interactions between a probe and the molecule. 

Carrupt, P.A., Gaillard, P., Billois, F., Weber, P., Testa, B., Meyer, C. and Perez, S. (1995) The Molecular lipophilicity potential (MLP) a new tool for logP calculation and docking, and in comparative molecular field analysis (CoMFA). In Pliska, V., Testa, B. and van de Waterbeemd, H. (eds). Lipophilicity in Drug Action and Toxicology, pp. 195-215. VCH, Weinheim. 

P.-A. Carrupt, P. Gaillard, F. Billois, P. C. Weber, B. Testa, C. Meyer, and S. Perez, in Lipophilicity in Drug Action and Toxicology, V. Pliska, B. Testa, and H. I n de ter-beemd, Eds., Methods and Principles in Medicinal Chemistry series, VCH Publishers, Weinheim, 1996, Vol. 4, pp. 195-217. The Molecular Lipophilicity Potential (MLP) A New Tool for log P Calculations and Docking and in Comparative Molecular Field Analysis. See also Ref. 16b. 

The molecular lipophilicity potential is a transformation of log Fo tanoi/watcr values (conceptually one-dimensional representations) into three-dimensional representations.The MLP describes the combined lipophilic influence of all fragments in a molecule on its environment and can be calculated at any given point in space around a molecule. Two components are needed to calculate a lipophilicity potential a fragmental system of lipophilicity22.86.95,us g d a distance function, as expressed by the following general equation ... 

Figure 11 A Fermi-type function used to calculate the molecular lipophilicity potential. (Ref. 155.)...

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-... 

Instead of using the oral bioavailability of a drug, one can attempt to correlate PM values with permeability coefficients generated from in situ perfused intestinal preparations. Here, one eliminates the complexities of liver metabolism, clearance, and formulation variables. Recently, this type of in vitro-in situ correlation has been conducted using the model peptides (described previously in Section V.B.2). The permeabilities of these model peptides were determined using a perfused rat intestinal preparation which involved cannulation of the mesenteric vein (Kim et al., 1993). With this preparation, it was possible to measure both the disappearance of the peptides from the intestinal perfusate and the appearance of the peptides in the mesenteric vein. Thus, clearance values (CLapp) could be calculated for each peptide. Knowing the effective surface area of the perfused rat ileum, the CLapp values could be converted to permeability coefficients (P). When the permeability coefficients of the model peptides were plotted as a function of the lipophilicity of the peptides, as measured by partition coefficients in octanol-water, a poor correlation (r2 = 0.02) was observed. A better correlation was observed between the permeabilities of these peptides and the number of potential hydrogen bonds the peptide can make with water (r2 = 0.56,... 

The relationship between the herbicidal activity of 1,2,5-oxadiazole iV-oxides and some physicochemical properties potentially related to this bioactivity, such as polarity, molecular volume, proton acceptor ability, lipophilicity, and reduction potential, were studied. The semi-empirical MO method AMI was used to calculate theoretical descriptors such as dipolar moment, molecular volume, Mulliken s charge, and the octanol/water partition coefficients (log Po/w) <2005MOL1197>. 

Potential for bioaccumulation Due to their high Log values and high fat blood partition coefficient, the cyclic siloxanes are likely to be stored into the lipid tissue. However, bioaccumulation is not dependent just on the lipophilicity of the compound, but also in how fast it leaves the contaminated organism. Other indicators of bioaccumulation are the bioconcentration factor (BCF) and bioaccumulation factor (BAF). Values over 5,000 are usually characteristic for the bioaccumulative compounds. D4 has a BCF of 12,400 L/kg [293], D5 of 7,060 L/kg [279], and D6 of 1,160 L/kg [280], values calculated for fish. 

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