Descriptor GRID molecular interaction fields

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.

Another class of 3D descriptors is molecular interaction field (MIF) descriptors, with its well-known example of Comparative Molecular Field Analysis (204,205) (CoMFA). In CoMFA, the steric and electrostatic fields are calculated for each molecule by interaction with a probe atom at a series of grid points surrounding the aligned molecules in 3D space. These interaction energy fields are correlated with the property of interest. The 3D nature of the CoMFA technique provides a convenient tool for visualization of the significant features of the resulting models. 

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.

The set of 51 benzamidine-based thrombin inhibitors was taken from the study of Sugano et al. (2000). Experimental rat everted sac permeabilities were expressed as log(ES A) values.2 The experimental permeability in this assay is expressed as ratio of outer (mucosal side) concentration of the drug and inner (serosal side) concentration after 1 h incubation of the everted sac of rat small intestine. All molecules were treated in their neutral form and converted into their 3D structures using CORINA (Sadowski et al. 1992). From GRID molecular interaction fields for water, dry, and carbonyl oxygen probes, a set of 72 VolSurf descriptors (Cruciani et al. 2000) was computed and analysed as described above. 

We have presented a netv procedure, called PathFinder, aimed at encoding the GRID molecular interaction fields into invariant shape-descriptors, suitable for similarity and complementarity issues. Shape similarity is the underlying foundation of ligand-based methods tvhile shape complementarity is the basis of many receptor-based designs. 

The molecular interaction fields (MIF) obtainable by GRID [1] may be used to define the solvent accessible surface, which resembles the molecular shape. However, MIFs are descriptors that depend on the 3D-location, and usually several thousand are required to describe a shape. In this chapter we present a novel procedure, called PathFinder, which encodes MIF into a compact alignment-free description of molecular shape. 

The procedure is called MetaSite (Site of Metabolism prediction) [25]. The MetaSite procedure is fully automated and does not require any user assistance. All the work can be handled and submitted in a batch queue. The molecular interaction fields for CYPs obtained from the GRID package are precomputed and stored inside the software. The semiempirical calculations, phaimacophoric recognition, descriptor handling, similarity computation, and reactivity computation are carried out automatically once the structures of the compounds are provided. The complete calculation is performed in a few seconds in IRIX SGI machines, and is even faster in the Linux or Windows environment. For example, processing a database of 100 compounds, starting from 3D molecular structures, takes about three minutes at full resolution with a... 

In - grid-based QSAR techniques, the energy value at each grid point p constitutes a molecular descriptor. For the selected -> molecular interaction fields (steric, hydrophobic, coulombic, etc.), the calculated value at each grid point p depends on the relative orientation of the compound with respect to the grid. As a consequence, the use of... 

These are QSAR techniques, sometimes also referred to as CoMFA-like approaches, based on descriptors defined as molecular interaction energy values representing - molecular interaction fields or, in other words, the interaction energy between a - probe and a target compound embedded in a grid. 

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. 

Unlike the other grid-based techniques, molecular descriptors are not derived from —> molecular interaction fields but from the partition of molecules into different parts that are expected to have different types of interactions with receptor sites. 

Besides the aforementioned descriptors, grid-based methods are frequently used in the field of QSAR quantitative structure-activity relationships) [50]. A molecule is placed in a box and for an orthogonal grid of points the interaction energy values between this molecule and another small molecule, such as water, are calculated. The grid map thus obtained characterizes the molecular shape, charge distribution, and hydrophobicity. 

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