Predictive three-dimensional quantitative structure-activity relationship of cytochrome P450 1A2 inhibitors.

The purpose of this study was to determine the cytochrome P450 1A2 (CYP1A2) inhibition potencies of structurally diverse compounds to create a comprehensive three-dimensional quantitative structure-activity relationship (3D-QSAR) model of CYP1A2 inhibitors and to use this model to predict the inhibition potencies of an external set of compounds. Fifty-two compounds including naphthalene, lactone and quinoline derivatives were assayed in a 96-well plate format for CYP1A2 inhibition activity using 7-ethoxyresorufin O-dealkylation as the probe reaction. The IC50 values of the tested compounds varied from 2.3 microM to over 40,000 microM. On the basis of this data set, a comparative molecular field analysis (CoMFA) and GRID/GOLPE models were created that yielded novel structural information about the interaction between inhibitory molecules and the CYP1A2 active site. The created CoMFA model was able to accurately predict inhibitory potencies of several structurally unrelated compounds, including selective inhibitors of other cytochrome P450 forms.