3D-QSAR CoMFA study on imidazolinergic I-2 ligands: A significant model through a combined exploration of structural diversity and methodology

Displaying an unprecedented structural diversity, 119 I-2 ligands, and thei r pK(i) values, were collected and submitted to a comparative molecular fie lds analysis (CoMFA) study. They were discerned into three structural subse ts (A, B, C), to explore the I-2 3D-QSARs from finite structural systems (A , B, C) to more complex ones (AB, AC, BC, ABC). In addition, various key st eps of the CoMFA methology were explored. The applied method used two pharm acophore templates and seven molecular field combinations (electrostatic, l ipophilic, steric), as well as eight alignment methods (two point-by-point and six similarity-based variations). That way, 644 CoMFA models were obtai ned and further selected according to their predictive ability through two filters. The first filter was mainly based on the q(2), which internally ev aluates the predictive ability from the training set. For the second filter , the predictive ability was externally evaluated through the prediction of test sets. Finally, one model was extracted from the whole data as the bes t. Indeed, it combines three features of upmost importance for the further design of ligands endowed with high It affinity: structural diversity (n = 73), robustness (N = 9, r(2) = 0.96, s = 0.28, F = 148), and a great fully assessed predictive ability (q(2) = 0.50, r(2) (test set) = 0.81, n(test se t) = 46). On the basis of structural data and CoMFA isocontours, some eleme nts of the It tridimensional pharmacophore are also suggested.