Integrated Virtual Screening Approach Identifies New CYP19A1 Inhibitors

The human cytochrome P450 19A1 (CYP19A1, aromatase) is
a heme-containing
protein catalyzing the final steps of the biosynthesis of the steroid
hormone 17β-estradiol. It is a key target for the treatment
of sex-hormone-related disorders due to its role in mediating the
conversion of androgens to estrogens. Here, we report the development
of a virtual screening workflow incorporating machine learning and
structure-based modeling that has led to the discovery of new CYP19A1
inhibitors. The machine learning models were built on comprehensive
CYP19A1 data sets extracted from the ChEMBL and PubChem Bioassay databases
and subjected to thorough validation routines. Ten promising hits
that resulted from the virtual screening campaign were selected for
experimental testing in an enzymatic assay based on heterologous expression
of human CYP19A1 in yeast. Among the seven structurally diverse compounds
identified as new CYP19A1 inhibitors, compound 9, a novel,
noncovalent inhibitor based on coumarin and imidazole substructures,
stood out by its high potency, with an IC50 value of 271
± 51 nM.