Theoretical quantitative structure-activity relationship analysis of congeneric and non-congeneric α1-adrenoceptor antagonists: a chemometric study

Molecular orbital calculations (AM1) and molecular modelling procedures (QUANTA/CHARMm) have been performed both on a congeneric (prazosin analogs) and on a non-congeneric series of alpha(1)-adrenergic antagonists. A large variety of theoretical molecular descriptors has been obtained and compared by principal component analysis (PCA). The generating optimal least squares estimations (GOLPE) procedure has been used to derive quantitative structure-activity relationships (QSARs). Good predictive QSAR models with a restricted pool of informative theoretical descriptors have been obtained. These results support the generality of the theoretical QSAR approach proposed; in fact both congeneric and non-congeneric molecular series were satisfactorily modeled. Moreover, the high and well-defined physical information content encoded in the theoretical descriptors considered allows the rationalization of the structural heterogeneity of the molecules examined as differences in the complementary intermolecular interactions of the studied ligands towards their common receptor.