Identification of CYP1A2 ligands by structure-based and ligand-based virtual screening

Abstract

The metabolic enzyme cytochrome P450 1A2 (CYP1A2) attracts much attention, not only because of its metabolism of drug compounds, but also due to its ability to convert procarcinogens to carcinogens. From a virtual screening, 41 compounds were selected and tested experimentally for inhibition of CYP1A2. Among these compounds, 16 inhibited the CYP1A2 activity by more than 50% at a concentration of 0.3 μM. The three most potent inhibitors have IC₅₀ values of 20 nM. These inhibitors contain new scaffolds and may serve as starting points for further lead optimization. Thus, the applied virtual screening methods are useful for considering CYP1A2 inhibition, either to identify inhibitors of CYP1A2, e.g. for cancer therapy, or to identify undesirable inhibitory effects of the enzyme.