A MULTIWAY 3D QSAR ANALYSIS OF A SERIES OF 1-ETHYL-2-PYRROLIDINYL)METHYL]-6-METHOXYBENZAMIDES

Recently, the multilinear PLS algorithm was presented by Bro and later implemented as a regression method in 3D QSAR by Nilsson et al. In th e present article a well-known set of -ethyl-2-pyrrolidinyl)methyl]-6- methoxybenzamides, with affinity towards the dopamine D-2 receptor sub type, was utilised for the validation of the multilinear PLS method. A fter exhaustive conformational analyses on the ligands, the active ana logue approach was employed to align them in their presumed pharmacolo gically active conformations, using (-)-piquindone as a template. Desc riptors were then generated in the GRID program, and 40 calibration co mpounds and 18 test compounds were selected by means of a principal co mponent analysis in the descriptor space. The final model was validate d with different types of cross-validation experiments, e.g. leave one -our, leave-three-out and leave-five-out. The cross-validated Q(2) was 62% for all experiments, confirming the stability of the model. The p rediction of the test set with a predicted Q(2) of 62% also establishe d the predictive ability. Finally, the conformations and the alignment of the ligands in combination with multilinear PLS, obviously, played an important role for the success of our model.