GRID probe interaction

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.

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. 

Grids of target-probe interaction energy values can be read into many molecular graphics programs which can display the MIFs as isoenergy contours or project the energies onto molecular surfaces. 

When a probe binds a target molecule, it may displace ordered water molecules and it may result in ordering of a flexible part of the protein. Both these events have entropic effects. To account for these, an entropy term has been included in more recent versions of GRID and takes different forms according to the type of calculation. It is computed when parts of the target are treated as flexible, when the probe interactions are compared to that of water, and for the hydrophobic probe, known as the DRY probe. 

A careful pretreatment is necessary to focus on the relevant variables. Often variables with low absolute values (<0.01 kcal moT ) and those with low standard deviations (<0.02-0.03kcal mol" ) are removed in order to eliminate noise. Autoscaling is not recommended, since all the data comes from the same source (GRID probe-target interaction energies) and all the data are expressed in the same units (kcalmof ). Thus, autoscaling might introduce noise in the model. 

The binding sites of aligned 3D structures are characterized, using five to ten GRID probes in order to encompass a diverse yet manageable set of interactions. The most frequently used probes include DRY (hydrophobic interactions), C3 (steric), N1 (H bond donor), O (H bond acceptor), and OH (H bond donor and acceptor). 

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