GRID interaction fields

Afzelius et al. (26) reported a study that describes the generation of a three-dimensional QSAR model for 25 competitive CYP2C9 inhibitors in the training set and 8 inhibitors in the test set. The GRID interaction fields using the DRY and OH probe were used as descriptors. The resulting predictive model... 

The overall prediction rate for the selective site of metabolism within the CYP2C subfamily based on the selective interaction profiling using the loading plots from a cPCA analysis based on flexible GRID interaction fields was 72.4%. 

Goodford, P. J. The basic principles of GRID. In Molecular Interaction Fields Application in Drug Discovery and ADME Prediction (Methods and Principles in Medicinal Chemistry), Cruciani, G., Mannhold, R. Kubinyi, H., Folkers, G. 

The interaction of drug molecules with biological membranes is a three-dimensional (3D) recognition that is mediated by surface properties such as shape, Van der Waals forces, electrostatics, hydrogen bonding, and hydrophobicity. Therefore, the GRID force field [5-7], which is able to calculate energetically favorable interaction sites around a molecule, was selected to produce 3D 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. 

Figure 12.2 The X-ray structure of human UGT2B7 (left) showing the UDPGA-binding site (left), and their molecular interaction fields (right) obtained using GRID force field [21], showing the large cavity and the hydrophilic regions (in blue).

Carosati, E., Sciabola, S. and Cruciani, G. (2004) Hydrogen bonding interactions of covalently bonded fluorine atoms from crystallographic data to a new angular function in the GRID force field. Journal of Medicinal Chemistry, 47, 5114-5125. 

Cruciani, G., Aristei, Y., Vianello, R. and Baroni, M. (2005) GRID-derived molecular interaction fields for predicting the site of metabolism in human cytochromes, in Molecular Interaction Fields (ed. G. Cruciani) Wiley-VCH Verlag GmbH, Weinheim, pp. 273-290. 

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. 

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. 

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,... 

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. 

The GRID program [44] has been used by a number of workers as an alternative to the original CoMFA method for calculating interaction fields. An advantage of the GRID approach, apart from the large number of chemical probes... 

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.

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