3D QSAR studies on T-type calcium channel blockers using CoMFA and CoMSIA Original Research Article

Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were performed on a series of isoxazolyl compounds as a potent T-type calcium channel blockers. A set of 24 structurally similar compounds served to establish the model. Four different conformations of the most active compound were used as template structures for the alignment, three of which were obtained from Catalyst pharmacophore modeling and one by using SYBYL random search option. All CoMFA and CoMSIA models gave cross-validated r2 (q2) value of more than 0.5 and conventional r2 value of more than 0.85. The predictive ability of the models was validated by an external test set of 10 compounds, which gave satisfactory pred r2 values ranging from 0.577 to 0.866 for all models. Best predictions were obtained with CoMFA std model of Conformer no: 3 alignment (q2=0.756, r2=0.963), giving predictive r2 value of 0.866 for the test set. CoMFA and CoMSIA contour maps were used to analyze the structural features of the ligands accounting for the activity in terms of positively contributing physicochemical properties: steric, electrostatic, hydrophobic and hydrogen bonding fields.