QSAR models of cytochrome P450 enzyme 1A2 inhibitors using CoMFA, CoMSIA and HQSAR.

Quantitative structure-activity relationship (QSAR) studies were conducted on an in-house database of cytochrome P450 enzyme 1A2 inhibitors using the comparative molecular field analysis (CoMFA), comparative molecular similarity analysis (CoMSIA) and hologram QSAR (HQSAR) approaches. The database consisted of 36 active molecules featuring varied core structures. The model based on the naphthalene substructure alignment incorporating 19 molecules yielded the best model with a CoMFA cross validation value q(2) of 0.667 and a Pearson correlation coefficient r(2) of 0.976; a CoMSIA q(2) value of 0.616 and r(2) value of 0.985; and a HQSAR q(2) value of 0.652 and r(2) value of 0.917. A second model incorporating 34 molecules aligned using the benzene substructure yielded an acceptable CoMFA model with q(2) value of 0.5 and r(2) value of 0.991. Depending on the core structure of the molecule under consideration, new CYP1A2 inhibitors will be designed based on the results from these models.