ArticleJournal of medicinal chemistry2013
Pyridine-substituted desoxyritonavir is a more potent inhibitor of cytochrome P450 3A4 than ritonavir.
Article in Journal of medicinal chemistry, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 33 papers.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Who cites it
33 citing papers in PubMed, 80 citations in OpenAlex.
- Binding Site Vectors Enable Mapping of Cytochrome P450 Functional Landscapes.Journal of chemical information and modeling · 2026Article
- Evaluation of Larger Side-Group Functionalities and the Side/End-Group Interplay in Ritonavir-Like Inhibitors of CYP3A4.Chemical biology & drug design · 2025Article
- A Computational Pipeline Observes the Flexibility and Dynamics of Plant Cytochrome P450 Binding Sites.International journal of molecular sciences · 2024Article
- Interaction of CYP3A4 with the inhibitor cobicistat: Structural and mechanistic insights and comparison with ritonavir.Archives of biochemistry and biophysics · 2024Article
- Water Exchange from the Buried Binding Sites of Cytochrome P450 Enzymes 1A2, 2D6, and 3A4 Correlates with Conformational Fluctuations.Molecules (Basel, Switzerland) · 2024Article
- Transgenic Expression ofInternational journal of molecular sciences · 2022Article
- Interaction of CYP3A4 with Rationally Designed Ritonavir Analogues: Impact of Steric Constraints Imposed on the Heme-Ligating Group and the End-Pyridine Attachment.International journal of molecular sciences · 2022Article
- The HIV protease inhibitor, ritonavir, corrects diverse brain phenotypes across development in mouse model of DYT-TOR1A dystonia.Science translational medicine · 2021Article
- Photosensitive Ru(II) Complexes as Inhibitors of the Major Human Drug Metabolizing Enzyme CYP3A4.Journal of the American Chemical Society · 2021Article
- Homotropic Cooperativity of Midazolam Metabolism by Cytochrome P450 3A4: Insight from Computational Studies.Journal of chemical information and modeling · 2021Article
- Rational Design of CYP3A4 Inhibitors: A One-Atom Linker Elongation in Ritonavir-Like Compounds Leads to a Marked Improvement in the Binding Strength.International journal of molecular sciences · 2021Article
- CYP2J2 Molecular Recognition: A New Axis for Therapeutic Design.Pharmacology & therapeutics · 2020Review
- Structure-guided manipulation of the regioselectivity of the cyclosporine A hydroxylase CYP-sb21 fromSynthetic and systems biotechnology · 2020Article
- Mechanistic Insights into the Regio- and Stereoselectivities of Testosterone and Dihydrotestosterone Hydroxylation Catalyzed by CYP3A4 and CYP19A1.Chemistry (Weinheim an der Bergstrasse, Germany) · 2020Article
- An increase in side-group hydrophobicity largely improves the potency of ritonavir-like inhibitors of CYP3A4.Bioorganic & medicinal chemistry · 2020Article
- Clobetasol Propionate Is a Heme-Mediated Selective Inhibitor of Human Cytochrome P450 3A5.Journal of medicinal chemistry · 2020Article
- Structural Perspectives of the CYP3A Family and Their Small Molecule Modulators in Drug Metabolism.Liver research (Beijing, China) · 2019Article
- Correction to "Allosteric Interactions in Human Cytochrome P450 CYP3A4: The Role of Phenylalanine 213".Biochemistry · 2019Article
- Probing membrane enhanced protein-protein interactions in a minimal redox complex of cytochrome-P450 and P450-reductase.Chemical communications (Cambridge, England) · 2019Article
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Authors and funding
2 authors at 1 institution in 1 country.
Funding
Abstract
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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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.