Molecular VolSurf

PETRA (calculation of physicochemical parameters) Molecular Networks GmbH, Nagelsbachstrasse 25, D-91052 Erlangen, Germany http //www.mol-net.de/ VolSurf Molecular Discovery Ltd., West Way House, Elms Parade, Oxford 0X2 9LL, UK http //www.moldiscovery.com/... 

A, B and V are constant for a given solute (Eig. 12.4 shows the value of A, 0.78, for atenolol). This means that the balance between intermolecular forces varies with the system investigated as would be expected from a careful reading of Section 12.1.1.3. This can also be demonstrated by using a completely different approach to factorize log P, i.e. a computational method based on molecular interaction fields [10]. Volsurf descriptors [11] have been used to calculate log P of neutral species both in n-octanol-water and in alkane-water [10]. 

Crudani, G., Crivori, P., Carrupt, P. A., Testa, B. Molecular fields in quantitative structure-permeation relationships the VolSurf approach. J. Mol. Struct. Theochem. 2000, 503, 17-30. 

Thus, a molecule can be characterized in terms of its potential hydrogen bonding, polar, hydrophobic and ionic interactions in 3D space. The size and the spatial distribution of these molecular interaction contours is translated into a quantitative scheme, the VolSurf descriptors, without the need to align the molecules in 3D space [8, 9] (Fig. 17.1). 

Fig. 17.1. Multivariate characterization with VolSurf descriptors. Molecular Interaction Fields (MIF shaded areas) are computed from the 3D-molecular structure. MIFs are transformed in a table of descriptors, and statistical multivariate analysis is performed.

The molecular descriptors refer to the molecular size and shape, to the size and shape of hydrophilic and hydrophobic regions, and to the balance between them. Hydrogen bonding, amphiphilic moments, critical packing parameters are other useful descriptors. The VolSurf descriptors have been presented and explained in detail elsewhere [8]. The VolSurf descriptors encode physico-chemical properties and, therefore, allow both for a design in the physico-chemical property space in order to rationally modulate pharmacokinetic properties, and for establishing quantitative structure-property relationships (QSPR). 

In the following section, the calculation of the VolSurf parameters from GRID interaction energies will be explained and the physico-chemical relevance of these novel descriptors demonstrated by correlation with measured absorption/ distribution/metabolism/elimination (ADME) properties. The applications will be shown by correlating 3D molecular structures with Caco-2 cell permeabilities, thermodynamic solubilities and metabolic stabilities. Special emphasis will be placed on interpretation of the models by multivariate statistics, because a rational design to improve molecular properties is critically dependent on an understanding of how molecular features influence physico-chemical and ADME properties. 

The VolSurf method was used to produce molecular descriptors, and PLS discriminant analysis (DA) was applied. The statistical model showed two significant latent variables after cross-validation. The 2D PLS score model offers a discrimination between the permeable and less permeable compounds. When the spectrum color is active (Fig. 17.2), red points refer to high permeability, whereas blue points indicate low permeability. There is a region in the central part of the plot with both red and blue compounds. In this region, and in between the two continuous lines, the permeability prediction is less reliable. The permeability model... 

The model interpretation is in good agreement with the known molecular factors influencing Caco-2 permeability. In addition - and this outlines the originality of the method - VolSurf allows the relevant 3D molecular properties to be quantified. Once the model is developed, as reported above, simple projection of the compound descriptors into it allows predictions to be made for new compounds. 

The VolSurf approach was used to correlate the 3D molecular descriptors by utilizing the water solubilities for as many compounds as could be found. Although over 2000 solubility values were identified, many showed contradictory results (both low and high values published). Moreover, some of the estimations had not been made by the authors and the original reference was not reported, while others were simply wrong, having not been measured under the standard conditions required. From the 2000 compounds, about 850 were carefully selected in addi-... 

Calculated molecular properties from 3D molecular fields of interaction energies are a novel approach to correlate 3D molecular structures with pharmacodynamic, pharmacokinetic and physico-chemical properties. The novel VolSurf descriptors quantitatively characterize size, shape, polarity, hydrophobicity and the balance between them. 

Crivori et al. [12] Molecular size, shape, polarity, hydrogen-bonding, and other Volsurf-generated variables... 

Fig. 14.5 Computation of VolSurf descriptors [155, 156] derived from GRID molecular interaction fields. Interactions of the example molecule with a water and dry probe at different contour levels are used to compute a vector of 72 volume-, size- and surface-based descriptors.

Cruciani et al., used a dynamic physicochemical interaction model to evaluate the interaction energies between a water probe and the hydrophilic and hydrophobic regions of the solute with the GRID force field. The VolSurf program was used to generate a PLS model able to predict log Poet [51] from the 3D molecular structure. 

Mannhold, R., Berellini, G., Carosati, E. and Benedetti, P. (2006) Use ofMlF-based VolSurf descriptors in physicochemical and pharmacokinetic studies, in Molecular Interaction Fields (ed. G. Crudani), Wiley-VCH, Weinheim,... 

VolSURF Molecular Discovery 185 http //www.moldiscovery.com/index.php... 

CoMFA, Molconn-Z, Volsurf (and other related products) Tripos Inc. www.tripos.com A variety of descriptors, including comparative molecular field analysis physicochemical properties and molecular, structural, and topological descriptors... 

Fig. 2. Computation of Volsurf descriptors (Cruciani et al. 2000a) derived from GRID molecular interaction fields. For any molecule, interactions with GRID water and dry probes at different energy levels are used for contouring. Those levels serve to compute vectors of 72 volume, size, and surface related descriptors.

Another modification of the VolSurf approach to analyze molecular interaction fields was described by Pastor et al. (2000). The same information previously been used to compute VolSurf descriptors now served to compute GRIND descriptors. In contrast to VolSurf, these descriptors capture information about pharmacophoric groups and their distances within individual molecules. These descriptors represent favorable interaction energy regions where groups... 

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