GRID/GOLPE

Sanz, F. 3D QSAR Methods on the Basis of Ligand-Receptor Complexes. Application of Combine and GRID/GOLPE Methodologies to a Series of CYP1A2 Inhibitors. /. Comput.-Aided Mol. Des. 2000, 13, 341-353. 

Figure 2.1. Results of chemometric analysis by the GRID/GOLPE method for23 different WW domains, (a) Plot of the predicted vs. experimental NMR chemical shift perturbation (CSP). (b) Important contributions to recognition of tyrosine-containing peptides are shown. The WW domain (WWP3-1) is...

The comparison of the GRID/GOLPE results with a ligand-based CoMFA model, (q loo value of 0.796) [60], indicated that the ligand alignment constructed on the basis of the receptor structure supplies a better explanation of the biological activities. This is also indicated by smaller deviations of the calculated from the experimental values in the receptor-based model [35]. 

To further validate the GRID/GOLPE model it was necessary to test its predictiv-ity for external test sets. We carefully checked the literature for further ER data sets, which were experimentally tested in the same assay under the same conditions [67-70], In order to test the general predictivity 36 structurally diverse ER ligands were selected from the mentioned studies (examples are shown in Fig. 7.3, the whole data set is described in detail in [36]). 

Table7.4. Designed compounds predicted using the GRID/GOLPE model.

In conclusion, we were able to design AChE inhibitors based on the docking and GRID/GOLPE study which seems to interact simultaneously with the cation-re subsite of the catalytic site and the peripheral site of the enzyme. Eurther support for our docking study came from the crystal structure of a novel Ach E-inhibitor complex [78]. The crystal structure of AChE complexed with the marketed drug donepezil was solved in 1999. Like donepezil, our most potent inhibitors contain a benzylpiperidine moiety which shows a similar position and orientation when compared with the published crystal structure. The comparison of both AchE-inhibitor complexes revealed that both kind of inhibitors adopt a comparable conformation in the narrow binding pocket [12]. As we predicted for our ami-... 

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