Lipophilicity potential, molecular

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.

Furet, P., Sele, A., Cohen, N. C. 3D molecular lipophilicity potential profiles a new tool in molecular modeling. J. 

Gaillard, P., Carrupt, P. A., Testa, B Boudon, A. Molecular lipophilicity potential, a tool in 3D QSAR Method and applications, f Comput.-Aided Mol. Des. 1994, 8, 83-96. 

It was an outstanding experience to plan, organize and realize this book, and to work with such a distinguished group of contributors. I hope that the readers will enjoy the work they did. I won new friends during this book project, one of which is Pierre-Alain Carrupt. He prepared the cover graphics, which represents the molecular lipophilicity potentials for my PhD molecule verapamil in its extended and folded conformation. 

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. 

LSER linear solvation energy relationship MLP molecular lipophilicity potential n mole number N neutral species... 

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). 

Molecular lipophilicity potential (MLP) has been developed as a tool in 3D-QSAR, for the visualization of lipophilicity distribution on a molecular surface and as an additional field in CoMFA studies [49]. MLP can also be used to estimate conformation-dependent log P values. 

Key Words 3D-QSAR hydrophobicity lipophilicity 3D-LogP conformation-dependent lipophilicity alignment-independent 3D descriptor molecular lipophilicity potential (MLP) ADME-related descriptor. 

More recently, the concept of the molecular lipophilicity potential (MLP), initially introduced by Audry and coworkers (2), has attracted increasing attention. The method involves mapping the local lipophilicity at points in 3D space around a chemical compound through the use of a parametrized fragmental system coupled to an empirical distance function. Despite the absence of any physical basis for the distance-dependent functions introduced, and the difficulties inher-... 

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

GaiUard, P., Carrupt, R A., Testa, B., and Schambel, R (1996) Binding of arylpiper-azines, (aryloxy)propanolamines and tetrahydropyridyl-indoles to the 5-HT1A receptor contribution of the molecular lipophilicity potential to three-dimensional quantitative structure-activity relationship models. J. Med. Chem. 39, 126-134. 

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. 

In addition to the steric and electrostatic descriptors, it was proposed to use other 3D molecular fields characterized by the sampling over the rectangular grid - in particular, the hydrophobic field/molecular lipophilic potential (MLP), ° hydrogen bonding and quantum-chemical parameters, e.g., orbital densities.Descriptor selection techniques are often recommended to enhance the stability, predictivity and interpretability of the CoMFA models. ... 

Finally, Figure 5.6(c) demonstrates the correspondence between effect of local lipophilicity Lg on activity (identified by the MFTA model) and the molecular lipophilic potential (MLP) of the protein. An increase of activity with increasing lipophilicity of ligand atoms (red circles) is found in the hydrophobic pocket area. In contrast, positions in the supergraph where activity is decreased by an increase in lipophilicity (blue circles) interact with relatively hydrophilic areas of the protein. 

Figure 5.6 Complementarity between the major MFTA descriptor contributions to activity of the TIBO inhibitors of HIV-1 reverse transcriptase and the molecular properties of the biotarget protein a) atomic charge (Q) and electrostatic potential (EP) (b) atomic van der Waals radius (i ) and molecular surface (c) local lipophilicity (Lg) and molecular lipophilic potential (MLP) - see text for details.

Furet, P, Sele, A. and Cohen, N.C. (1988). 3D Molecular Lipophilicity Potential Profiles A New Tool in Molecular Modeling. J.MoLGraphics, 6,182-189. 

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. 

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