Understanding the Role of CYP3A7 in Drug Metabolism to Advance Drug Discovery in Pediatric Populations

Authors

• MS Kabir
• S Sakamuru
• E Gonzalez
• R Huang
• EC Padilha
• J Braisted
• AQ Wang
• M Xia
• X Xu
• P Shah

Abstract

Cytochrome P450 (CYP) 3A4 is one of the most abundant and important xenobiotic metabolizing enzyme in adults. On the other hand, CYP3A7 accounts for about 50% of total CYP content in human embryonic, fetal, and newborn livers (25 weeks of gestation to 2 years old). There is a lack of understanding regarding CYP3A7-mediated metabolism. Our objective is to identify potential CYP3A7 substrates and inhibitors with the ultimate goal of advancing drug discovery in pediatric populations. We evaluated the differences in binding via Promega P450-Glo competitive inhibition assay for 5000 compounds which included the NCATS Pharmaceutical Collection (NPC) library (2800 compounds; collection of approved and investigational drugs), and an in-house library (2200 compounds; drug like molecules). A subset of 1000 compounds were chosen randomly for the CYP3A7 and CYP3A4 supersomes metabolic stability assay. From our P450-Glo assay, we identified 783 CYP3A7 selective inhibitors, 587 CYP3A4 selective inhibitors and 2216 common inhibitors. From the metabolic stability assay, we determined 37 compounds that were only metabolized by CYP3A7, 127 compounds by CYP3A4 and 87 compounds by both enzymes. Combining the data from these two assays, we were able to differentiate the substrates from probable inhibitors. From our preliminary experiments, we have shown that there is a clear difference between how compounds interact with CYP3A7 and CYP3A4. Our next goal is to develop a quantitative-structure activity relationship (QSAR) model. The dataset as well as the final model will be available to the public on the NCATS web app: https://predictor.ncats.io.

Scientific Focus Area: Molecular Pharmacology

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