title: A multiway 3D QSAR analysis of a series of (S)-N-[(1-ethyl-2-pyrrolidinyl)methyl]-6-methoxybenzamides.
abstract: Recently, the multilinear PLS algorithm was presented by Bro and later implemented as a regression method in 3D QSAR by Nilsson et al. In the present article a well-known set of (S)-N-[(1-ethyl-2-pyrrolidinyl)methyl]-6-methoxybenzamides, with affinity towards the dopamine D2 receptor subtype, was utilised for the validation of the multilinear PLS method. After exhaustive conformational analyses on the ligands, the active analogue approach was employed to align them in their presumed pharmacologically active conformations, using (-)-piquindone as a template. Descriptors were then generated in the GRID program, and 40 calibration compounds and 18 test compounds were selected by means of a principal component analysis in the descriptor space. The final model was validated with different types of cross-validation experiments, e.g. leave-one-out, leave-three-out and leave-five-out. The cross-validated Q2 was 62% for all experiments, confirming the stability of the model. The prediction of the test set with a predicted Q2 of 62% also established 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.
authors.affiliation: Department of Structural Chemistry, Pharmacia & Upjohn, Uppsala, Sweden.
authors.forename: J
authors.initials: J
authors.lastname: Nilsson
authors.forename: E J
authors.initials: EJ
authors.lastname: Homan
authors.forename: A K
authors.initials: AK
authors.lastname: Smilde
authors.forename: C J
authors.initials: CJ
authors.lastname: Grol
authors.forename: H
authors.initials: H
authors.lastname: Wikström
mesh_terms: D000465:Algorithms; D001549:Benzamides / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D003198:Computer Simulation; D018492:Dopamine Antagonists / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D065127:Dopamine D2 Receptor Antagonists; D008024:Ligands; D008958:Models, Molecular; D008968:Molecular Conformation; D017448:Receptors, Dopamine D2 / Q000378:metabolism; D013329:Structure-Activity Relationship; D013816:Thermodynamics
chemical_list: D001549:Benzamides; D018492:Dopamine Antagonists; D065127:Dopamine D2 Receptor Antagonists; D008024:Ligands; D017448:Receptors, Dopamine D2