3D-QSAR CoMFA study on imidazolinergic I2 ligands:: A significant model through a combined exploration of structural diversity and methodology

Displaying an unprecedented structural diversity, 119 I-2 ligands, and their pK(i) values, were collected and submitted to a comparative molecular fields analysis (CoMFA) study. They were discerned into three structural subsets (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 steps of the CoMFA methology were explored. The applied method used two pharmacophore templates and seven molecular field combinations (electrostatic, lipophilic, steric), as well as eight alignment methods (two point-by-point and six similarity-based variations). That way, 644 CoMFA models were obtained and further selected according to their predictive ability through two filters. The first filter was mainly based on the q(2), which internally evaluates 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 best. 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 set) = 46). On the basis of structural data and CoMFA isocontours, some elements of the It tridimensional pharmacophore are also suggested.