Dietary Inhibitors of CYP3A4 Are Revealed Using Virtual Screening by Using a New Deep-Learning Classifier

CYP3A4 is the main
human enzyme responsible for phase I metabolism
of dietary compounds, prescribed drugs and xenobiotics, steroid hormones,
and bile acids. The inhibition of CYP3A4 activity might impair physiological
mechanisms, including the endocrine system and response to drug admission.
Here, we aimed to discover new CYP3A4 inhibitors from food and dietary
supplements. A deep-learning model was built that classifies compounds
as either an inhibitor or noninhibitor, with a high specificity of
0.997. We used this classifier to virtually screen ∼60,000
dietary compounds. Of the 115 identified potential inhibitors, only
31 were previously suggested. Many herbals, as predicted here, might
cause impaired metabolism of drugs, and endogenous hormones and bile
acids. Additionally, by applying Lipinski’s rules of five,
17 compounds were also classified as potential intestine local inhibitors.
New CYP3A4 inhibitors predicted by the model, bilobetin and picropodophyllin,
were assayed in vitro.