Quantitative structure-activity relationships (QSARs) for substrates of human cytochromes P450 CYP2 family enzymes

The results of quantitative structure-activity relationship (QSAR) studies on substrates of human CYP2 family enzymes are reported, together with those of a small number of CYP2A6, CYP2C19 and CYP2D6 inhibitors. In general, there are good correlations (R = 0.90-0.99) between binding affinity (based on Km or KD values) and various parameters relating to active site interactions such as hydrogen bonding and pi-pi stacking. There is also evidence for the role of compound lipophilicity (as determined by either log P or log D7.4 values) in overall substrate binding affinity, and this could reflect the desolvation energy involved in substrate interaction within the enzyme active site. It is possible to estimate the substrate binding energy for a given P450 from a combination of energy terms relating to hydrogen bonding, pi-pi stacking, desolvation and loss in rotatable bond energy, which agree closely (R = 0.98) with experimental data based on either Km or KD values. Consequently, it is likely that active site interactions represent the major contributory factors to the overall binding affinities for human CYP2 family substrates and, therefore, their estimation is of potential importance for the development of new chemical entities (NCEs) as this can facilitate an assessment of likely metabolic clearance.