Comparative molecular field analysis and QSAR on substrates binding to cytochrome p450 2D6

In this study, we utilized comparative molecular field analysis (CoMFA) to gain a better understanding of the steric and electrostatic features of the cytochrome P450 2D6 (CYP2D6) active site. The training set consists of 24 substrates with reported K_M values from liver microsomal CYP2D6 spanning an activity range of almost three log units. The low energy conformers were fit by root mean square (RMS) to minaprine at the site of metabolism and to the protonated nitrogen. In this manner, we constructed two CoMFA models, one model with a distance constraint and another without. The model with the distance parameter (non-crossvalidated R²=0.99) was approximately equal to the CoMFA without a distance parameter (non-cross-validated R²=0.98). Validation of our CoMFA was accomplished by predicting the K_M values of 15 diverse CYP2D6 substrates not in the original training set resulting in a predictive R²=0.62. Finally, we also pursued correlations of pK_a and log P with CYP2D6 substrate K_M in an effort to investigate other physicochemical properties.