A molecular model of CYP2D6 constructed by homology with the CYP2C5 crystallographic template: investigation of enzyme-substrate interactions.

The results of homology modelling of CYP2D6 based on the mammalian P450 crystal structure of rabbit CYP2C5 are reported. It is found that many CYP2D6-selective substrates are able to fit closely within the putative active site of the enzyme where there are favourable contacts with complementary amino acid residues, including aspartate-301 which has been probed via site-directed mutagenesis. The homology model of CYP2D6 is consistent with available experimental evidence from selective substrate metabolism and site-specific mutation data. Quantitative structure-activity relationships (QSARs) with substrate binding affinity based on KD values and inhibition data (Ki values) demonstrate the importance of hydrogen bonding, pi-pi stacking and relative molecular mass in describing variations in avidity towards the CYP2D6 enzyme, although the compound lipophilicity (log D(7.4)) appears to be the most important single descriptor for CYP2D6 inhibition. Calculation of substrate binding affinity based on contributions from active site interactions and lipophilic character gives satisfactory agreement with experimentally determined KD values.