Decoding the selective chemical modulation of CYP3A4

Jingheng Wang, Stanley Nithianantham, Sergio C. Chai, Young-Hwan Jung, Lei Yang, Han Wee Ong, Yong Li, Yifan Zhang, Darcie J. Miller and Taosheng Chen ()
Additional contact information
Jingheng Wang: St. Jude Children’s Research Hospital
Stanley Nithianantham: St. Jude Children’s Research Hospital
Sergio C. Chai: St. Jude Children’s Research Hospital
Young-Hwan Jung: St. Jude Children’s Research Hospital
Lei Yang: St. Jude Children’s Research Hospital
Han Wee Ong: St. Jude Children’s Research Hospital
Yong Li: St. Jude Children’s Research Hospital
Yifan Zhang: St. Jude Children’s Research Hospital
Darcie J. Miller: St. Jude Children’s Research Hospital
Taosheng Chen: St. Jude Children’s Research Hospital

Nature Communications, 2025, vol. 16, issue 1, 1-19

Abstract: Abstract Drug-drug interactions associate with concurrent uses of multiple medications. Cytochrome P450 (CYP) 3A4 metabolizes a large portion of marketed drugs. To maintain the efficacy of drugs metabolized by CYP3A4, pan-CYP3A inhibitors such as ritonavir are often co-administered. Although selective CYP3A4 inhibitors have greater therapeutic benefits as they avoid inhibiting unintended CYPs and undesirable clinical consequences, the high homology between CYP3A4 and CYP3A5 has hampered the development of such selective inhibitors. Here, we report a series of selective CYP3A4 inhibitors with scaffolds identified by high-throughput screening. Structural, functional, and computational analyses reveal that the differential C-terminal loop conformations and two distinct ligand binding surfaces disfavor the binding of selective CYP3A4 inhibitors to CYP3A5. Structure-guided design of compounds validates the model and yields analogs that are selective for CYP3A4 versus other major CYPs. These findings demonstrate the feasibility to selectively inhibit CYP3A4 and provide guidance for designing better CYP3A4 selective inhibitors.

Date: 2025
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DOI: 10.1038/s41467-025-58749-8

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