期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 56, 期 9, 页码 3733-3741出版社
AMER CHEMICAL SOC
DOI: 10.1021/jm400288z
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资金
- National Institutes of Health [GM33688]
- Gilead Sciences, Inc.
- California Center for Antiviral Drug Discovery
- Department of Energy, Office of Biological and Environmental Research
- National Institutes of Health, National Center for Research Resources, Biomedical Technology Program
- National Institute of General Medical Sciences
Utilization of the cytochrome P450 3A4 (CYP3A4) inhibitor ritonavir as a pharmacoenhancer for anti-HIV drugs revolutionized the treatment of HIV infection. However, owing to ritonavir-related complications, there is a need for development of new CYP3A4 inhibitors with improved pharmacochemical properties, which requires a full understanding of the CYP3A4 inactivation mechanisms and the unraveling of possible inhibitor binding modes. We investigated the mechanism of CYP3A4 interaction with three desoxyritonavir analogues, containing the heme-ligating imidazole, oxazole, or pyridine group instead of the thiazole moiety (compounds 1, 2, and 3, respectively). Our data show that compound 3 is superior to ritonavir in terms of binding affinity and inhibitory potency owing to greater flexibility and the ability to adopt a conformation that minimizes steric clashing and optimizes protein-ligand interactions. Additionally, Ser119 was identified as a key residue assisting binding of ritonavir-like inhibitors, which emphasizes the importance of polar interactions in the CYP3A4-ligand association.
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