GRID-related 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.

Nevertheless, the prediction of the pharmacokinetic profile from the chemical structure reported in Fig. 10.1 is still a challenging task that remains partially unsolved. GRID-MIF descriptors were successfully applied to a lot of related subproblems helping to address practical work during the drug discovery process. 

In addition to the VolSurf treatment of the GRID fields, the information from the MIF can also be transformed to obtain a pharmacophoric type of representation, which is useful in the modeling of metabolic stability, cytochrome inhibition or even the direct study of the ADME related proteins (Fig. 10.3). The Almond software [17] transforms the MIF into a distance-based representation of the molecule interaction. These parameters describe the geometry of the interaction and QSAR models can be derived where the interaction with a protein is essential. Detailed information on these descriptors is presented elsewhere in this book. 

Moreover GRID can be used to understand the structural differences related to enzyme selectivity, a fundamental field in the rational design of drugs. GRID maps can also be used as descriptor input in statistical procedures like CoMFA, GOLPE or SIMCA for QSAR or 3D-QSAR analyses. 

The most popular grid-based QSAR techniques are - GRID method and -> CoMFA a number of related techniques has also been proposed such as - CoMSIA, - Voronoi Molecular Field Analysis, -> hydration free energy density, and the approach based on - G-WHIM descriptors. 

The stereoelectronic representation (or lattice representation) of a molecule is a molecular description related to those molecular properties arising from electron distribution - interaction of the molecule with probes characterizing the space surrounding them (e.g. - molecular interaction fields). This representation is typical of - grid-based QSAR techniques. Descriptors at this level can be considered 4D-descriptors, being characterized by a scalar field, i.e. a lattice of scalar numbers associated with the 3D - molecular geometry. 

This is 3D-QSAR technique proposed to overcome the drawbacks of the - grid-based QSAR techniques such as -> CoMFA related to the superimposition of the molecules. The descriptors produced by this method do not require - alignment rules and are not... 

It is clear that for an unsymmetrical data matrix that contains more variables (the field descriptors at each point of the grid for each probe used for calculation) than observables (the biological activity values), classical correlation analysis as multilinear regression analysis would fail. All 3D QSAR methods benefit from the development of PLS analysis, a statistical technique that aims to find the multidimensional direction in the X space that explains the maximum multidimensional variance direction in the F space. PLS is related to principal component analysis (PCA)." ° However, instead of finding the hyperplanes of maximum variance, it finds a linear model describing some predicted variables in terms of other observable variables and therefore can be used directly for prediction. Complexity reduction and data... 

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