Pharmacophore GRID probe

Figure 4.7. The complementaiy site points used for pharmacophore fingerprint calculations (lower right), together with the energetically favorable contours from 5 GRID probes on a FactorXa binding site.

The descriptors developed to characterize the substrate chemotypes are obtained from a mixture of molecular orbital calculations and GRID probe-pharmacophore recognition. Molecular orbital calculations to compute the substrate s electron density distribution are the first to be performed. All atom charges are determined using the AMI Hamiltonian. Then the computed charges are used to derive a 3D pharmacophore based on the molecular electrostatic potential (MEP) around the substrate molecules. 

Figure 16.5 Resulting pharmacophore for P-gp actively transported molecules. The depicted molecule is the analgesic (narcotic) sufentanil. The colored areas around the molecules are the GRID fields produced by the molecule yellow for DRY probe, green for TIP probe and blue for N1 probe. Reprinted with permission from ref. [53], Copyright 2005 American Chemical Society.

Figure 16.6 A graphical representation of the most important 3D pharmacophoric GRIND features for the cimetidine substrate as a reference compound. The colored areas around the molecule are the GRID MIFs calculated with the O (red) and N1 (blue) probes. Reprinted with permission from ref. [54]. Copyright 2006 American Chemical Society.

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. 

Condense the information contained in the GRID map into fewer target-based pharmacophoric points. These pharma-cophoric points are selected to encompass the minimum energy regions for the different probes and to cover the different regions of the binding site. 

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