Human CYPs involved in drug metabolism: structures, substrates and binding affinities

There is current interest in the CYPs primarily due to their important role in the Phase I metabolism of foreign compounds, including pharmaceuticals, agrochemicals and environmental pollutants, to which mankind is exposed.

The roles of the human CYPs are introduced in the context of using structural modelling and quantitative structure-activity relationships for rationalizing substrate binding, selectivity and rates of metabolism, particularly for drugs in current clinical use. The importance of compound lipophilicity in both substrate binding and metabolic rate is emphasised, together with the employment of an automated docking method (AutoDock) for estimating binding energy and likely route of metabolism for drug substrates.

The location of key interacting groups on both substrate and enzyme tends to define the preferred outcome of CYP-mediated drug metabolism in the majority of cases investigated thus far. This enables one to draw up a simple model of the important features present in the binding sites of CYPs which relate to substrate selectivity and likely positions of metabolism.

For the major CYPs involved in human drug metabolism, it would appear that there is a relatively well-defined key distance, in terms of number of intervening atoms, between the main sites of binding and CYP-mediated metabolism.