GRID molecular interaction fields

Cruciani et al. [92] have developed the program Metasite for the prediction of the site of oxidative metabolism by CYP450 enzymes. Metasite uses GRID molecular interaction fields to fingerprint both structures of CYP450s (from homology models or crystal structures) and test substrates and then matches the fields. Zhou et al. [93] showed that Metasite was able to correctly predict the site(s) of metabolism 78% of the time for 227 CYP3A4 substrates. Caron et al. [94] used Metasite to predict the oxidative metabolism of seven statins. 

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.

Ahlstrom, M.M., Ridderstrom, M., Luthman, K. and Zamora, I. (2005) Virtual screening and scaffold hopping based on GRID molecular interaction fields. fournal of Chemical Information and Modeling, 45, 1313-1323. 

Milletti, E., Storchi, L., Sforna, G. and Cruciani, G. (2007) New and original pKa prediction method using grid molecular interaction fields. Journal of Chemical Information and Modeling, 47,... 

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. 

The absence of a precise shape description, based on the GRID molecular interaction fields, prompted the development of a new procedure, called PathFinder, that is described here. 

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. 

I 70 Progress in ADME Prediction Using GRID-Molecular Interaction Fields... 

Figure 10.3. Transformation ofthe GRID molecular interaction fields into...

I 70 Progress in ADME Prediction Using GRID-Molecular Interaction Fields Table 10.6. CYP2C18 substrates. The experimentally determined site of metabolism. 

There are several ways in which GRID molecular interaction fields can be used in the ADME area ... 

CYPs Characterization using GRID Molecular Interaction Fields I 277... 

Harpsoe K, Liljefors T, Balle T (2008) Prediction of the binding mode of biarylpropylsulfo-namide allosteric AMPA receptor modulators based on docking, GRID molecular interaction fields and 3D-QSAR analysis. J Mol Graph Model 26 874-883... 

F. Milletti, L. Storchi, G. Sfoma, and G. Cruciani, New and original pK prediction method using grid molecular interaction fields, J. Chem. Inf. Model. 47 (2007), pp. 2172-2181. 

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