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.本研究开发了一种基于SMARTCyp方法的基于配体的预测方法，可对细胞色素P450 2D6（cytochrome P450 2D6）介导的类药分子代谢位点进行预测。该方法除使用SMARTCyp所计算的反应活性外，仅需两类额外描述符：分别为与质子化氮原子的空间距离，以及与分子末端的空间距离。因此，该方法可直接通过分子的二维结构预测代谢位点，无需进行电子性质计算或三维结构的生成。在独立测试集上开展的验证实验显示，其曲线下面积（area under the curve, AUC）达0.94，且针对91%的化合物，其代谢位点可被包含在排名前两位的原子之列。