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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Vydáno v:	Nature communications Ročník 16; číslo 1; s. 3423 - 19
Hlavní autoři:	Wang, Jingheng, Nithianantham, Stanley, Chai, Sergio C., Jung, Young-Hwan, Yang, Lei, Ong, Han Wee, Li, Yong, Zhang, Yifan, Miller, Darcie J., Chen, Taosheng
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	London Nature Publishing Group UK 10.04.2025 Nature Publishing Group Nature Portfolio
Témata:	13/106 38/47 631/154/1435/2163 631/535/1266 631/92/609 639/638/92/607 82/80 82/83 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
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Shrnutí:	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.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23
ISSN:	2041-1723 2041-1723
DOI:	10.1038/s41467-025-58749-8