GRID water probe

Fig. 3. Correlation of VolSurf descriptors with human intestinal absorption using multivariate statistics (PLS) based on 20 drug molecules as reported by Cuba et al. (2000). The PLS plot (ul versus tl) and the corresponding PLS coefficient plot is shown. Different interaction pattern with the GRID water probe are displayed for the orally available nordiazepam (left) versus the large area for the non-available...

Volumes of interactions with GRID water probe at eight energy levels (- 0.2 to - 6.0 kcal/mol)... 

Observed pKj, Torpedo califomica. Predicted pKj using the GRID water probe. 

Fig. 6. Kainate-iGluR2-SlS2 complex, including isoenergy contours according to GRID (16) - methyl probe (beige, -3.0 kcal/mol), water probe (cyan, -10.0 kcal/mol), and anionic oxygen probe (magenta, -11.0 kcal/mol).

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. 

Similar to the theoretical model of Palm et al. [54], based on dynamic surface properties for the prediction of drug absorption into human intestinal Caco-2 cell lines the authors used their molecular dynamics/GRID approach to correlate the absorption of the same set of six P-adrenoceptor antagonists with the coefficients obtained by the water probe at contour level -2 and -3 kcal/mol. 

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.

It has been shown how shape-related molecular description can be extracted starting from the GRID positive MIF. Similarly, the nodes of attractive interaction between the probe and the molecule (negative MIF) can be handled. The red isocontour surfaces in Fig. 5.4 represent the interaction of methotrexate with the water probe. In this case the application of the procedure described above will highlight the relative position on the molecular surface of the chemical moiety interacting with the water probe. The representation in Fig. 5.4(b) is not a strict shape function but more a new pharmacophoric representation of the molecule. 

Figure 7.9. PLS coefificient maps obtained using the water probe (a) and the methyl probe (b). Opaque fields are contoured at -0.003, grid fields are contoured at t-0.003 (compound 4j is shown for comparison).

Solubility is a key property in the distribution of the compound from the gastrointestinal tract to the blood. There have been several modeling efforts to predict the solubility, based on different type of descriptors. The intrinsic solubility (thermodynamic solubility of the neutral species) for a set of 1028 compounds has been modeled using the VolSurf descriptors based on GRID-MIFs (Fig. 10.9(a)) and PLS multivariate analysis [20]. The interpretation of the model can be based on the PLS coefficients the ratio of the surface that has an attractive interaction with the water probe contributes positively to the solubility, while the hydrophobic interactions and log P have a negative contribution. 

The main advantage of the GRID method is the great variety of available probes, represented by several functional groups such as water, methyl, ammonium, carboxy-late, and benzene in particular, among them there are probes which can both accept and donate a hydrogen bond (e.g. water), probes which cannot turn around (e.g. carbonyl probe), and a recently proposed hydrophobic probe, named DRY. 

Figure IS. (a) Stereoview of the contour at —5 kcal/mol for the GRID calculation using a water probe (cyan) and the HIV-1 protease crystal structure [72]. Inhibitor 29 (yellow, first binding mode), an inserted water molecule (red), and Asp29 (magenta) are shown, (b) Stereoview of the contour at —5 kcal/mol for the GRID calculation using a water probe (cyan) and the HIV-l protease crystal structure [72]. Inhibitor 29 (yellow, second binding mode), an inserted water molecule (red), and Gly48 (magenta) are shown.

Goodford recently added a hydrophobic (DRY) probe ° to the GRID program. This DRY probe could be used to explore hydropathic interactions and is likely to replace the water probe in GRID/CoMFA studies. 

One of the first studies to predict log P by using potential energy fields calculated using the GRID and CoMFA approaches was done by Kim [60]. The author investigated H, CH3 and H2O probes, and calculated the best models using the hydro-phobic probe H2O for relatively small series (20 or less compounds each) of furans, carbamates, pyridines and pyrazines. A similar study was performed by Waller [61] who predicted a small series of 24 polyhalogenated compounds. Recently, Caron and Ermondi [62] used a new version of Cruciani s software, VolSurf [63], to predict the octanol-water and alkane-water partition coefficients for 152 compounds with r = 0.77, q = 0.72, SDEP = 0.60 for octanol-water and r = 0.76, q = 0.71, SDEP = 0.85 for alkane-water. 

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.

A microwave oven equipped with Pello 3420 Load Cooler attachment is set at 25°C and full power. Two beakers, each filled with 500 ml of water, are placed in previously determined hot spots in the microwave oven (see pages 102-103). Grids containing the thin cryosections are floated (section side down) sequentially on small drops of 0.15% glycine and 1% BSA for 15 sec and 5 min, respectively. The reagent drops are placed on a clean disposable plastic surface which has been placed on the cold spot in the oven (an area between the two beakers of water). The local temperature is controlled using the microwave temperature probe immersed in a tube of water placed close to the grids. 

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