Modelling cytochromes P450 binding modes to predict P450 inhibition, metabolic stability and isoform selectivity

The cytochromes P450 (P450) superfamily is a diverse group of enzymes involved in the metabolism of xenobiotics, whose orientations within the catalytic site can lead to different binding modes, namely productive, nonproductive, and inhibitory. This article collects the most recent approaches that individually study P450-ligand interactions, including a novel in silico technology, developed in the framework of the Human Cytochrome P450 Consortium initiative, that provides reliable in silico predictions of P450 inhibition, metabolic stability and isoform selectivity.

Graphical abstractFigure optionsDownload full-size imageDownload high-quality image (281 K)Download as PowerPoint slideHighlights► P450 Binding Mode (BM) is how the ligand ‘approaches’ the heme. ► BMs are ranked according to the accessibility of corresponding atoms/groups. ► Metabolism and inhibition come from competition between BMs. ► Metabolism occurs when a BM is productive. ► P450 inhibition might be due to type II, time-dependent, productive or nonproductive BMs.