Decoding the selective chemical modulation of CYP3A4

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...

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Bibliographic Details
Published in:Nature communications Vol. 16; no. 1; pp. 3423 - 19
Main Authors: Wang, Jingheng, Nithianantham, Stanley, Chai, Sergio C., Jung, Young-Hwan, Yang, Lei, Ong, Han Wee, Li, Yong, Zhang, Yifan, Miller, Darcie J., Chen, Taosheng
Format: Journal Article
Language:English
Published: London Nature Publishing Group UK 10.04.2025
Nature Publishing Group
Nature Portfolio
Subjects:
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631/154/1435/2163
631/535/1266
631/92/609
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Binding
Cytochrome P-450 CYP3A - chemistry
Cytochrome P-450 CYP3A - genetics
Cytochrome P-450 CYP3A - metabolism
Cytochrome P-450 CYP3A Inhibitors - chemistry
Cytochrome P-450 CYP3A Inhibitors - pharmacology
Cytochrome P450
Cytochromes P450
Drug interaction
Drug Interactions
Drugs
Effectiveness
High-throughput screening
High-Throughput Screening Assays
Homology
Humanities and Social Sciences
Humans
Inhibitors
Ligands
multidisciplinary
Protein Binding
Ritonavir
Science
Science (multidisciplinary)
Structure-function relationships
ISSN:2041-1723, 2041-1723
Online Access:Get full text
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Summary: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. To maintain the efficacy of drugs metabolized by CYP3A4, pan-CYP3A inhibitor is often co-administered, but the high homology between CYP3A4 and CYP3A5 has hampered the development of selective CYP3A4 inhibitors. Here, the authors report a series of selective CYP3A4 inhibitors and show that differential C-terminal loop conformations and two distinct ligand binding surfaces disfavour the binding of selective CYP3A4 inhibitors to CYP3A5.
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ISSN:2041-1723
2041-1723
DOI:10.1038/s41467-025-58749-8