Ligand-Based Site of Metabolism Prediction for Cytochrome P450 2D6

A ligand-based method based on the SMARTCyp approach that predicts the sites of cytochrome P450 2D6-mediated metabolism of druglike molecules has been developed. The method uses only two descriptors besides the reactivity from SMARTCyp: the distance to a protonated nitrogen atom and the distance to the end of the molecule. Hence, the site of metabolism is predicted directly from the 2D structure of a molecule, without requiring calculation of electronic properties or generation of 3D structures. Testing on an independent test set gives an area under the curve value of 0.94, and a site of metabolism is found among the top two ranked atoms for 91% of the compounds.