ArticleMolecular pharmacology2013
Antifungal Azoles: Structural Insights into Undesired Tight Binding to Cholesterol-Metabolizing CYP46A1.
Article in Molecular pharmacology, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to trial NCT03706885 (A Proof-of-Concept Clinical Research Study of Efavirenz in Patients With Alzheimer's Disease), which is not on this map. Cited by 36 papers.
What it found
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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.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
A Proof-of-Concept Clinical Research Study of Efavirenz in Patients With Alzheimer's Disease
Who cites it
36 citing papers in PubMed, 77 citations in OpenAlex.
- Azole resistance in Aspergillus fumigatus- comprehensive review.Archives of microbiology · 2024Review
- Old and new strategies in therapy and diagnosis against fungal infections.Applied microbiology and biotechnology · 2024Review
- Resurgence and Repurposing of Antifungal Azoles by Transition Metal Coordination for Drug Discovery.Pharmaceutics · 2023Review
- Superficial Dermatophytosis across the World's Populations: Potential Benefits from Nanocarrier-Based Therapies and Rising Challenges.ACS omega · 2023Review
- Synthesis and clinical application of new drugs approved by FDA in 2022.Molecular biomedicine · 2023Review
- Fexinidazole interferes with the growth and structural organization of Trypanosoma cruzi.Scientific reports · 2022Article
- The Hydroxylation Position Rather than Chirality Determines How Efavirenz Metabolites Activate Cytochrome P450 46A1 In Vitro.Drug metabolism and disposition: the biological fate of chemicals · 2022Article
- Identification of potential inhibitors of brain-specific CYP46A1 from phytoconstituents in Indian traditional medicinal plants.Journal of proteins and proteomics · 2022Article
- Chromenol Derivatives as Novel Antifungal Agents: Synthesis, In Silico and In Vitro Evaluation.Molecules (Basel, Switzerland) · 2021Article
- Article
- An Integrated Approach to Identify New Anti-Filarial Leads to Treat River Blindness, a Neglected Tropical Disease.Pathogens (Basel, Switzerland) · 2021Article
- Cholesterol Hydroxylating Cytochrome P450 46A1: From Mechanisms of Action to Clinical Applications.Frontiers in aging neuroscience · 2021Review
- Sterol 14α-Demethylase Ligand-Binding Pocket-Mediated Acquired and Intrinsic Azole Resistance in Fungal Pathogens.Journal of fungi (Basel, Switzerland) · 2020Review
- Review
- In Vitro Activation of Cytochrome P450 46A1 (CYP46A1) by Efavirenz-Related Compounds.Journal of medicinal chemistry · 2020Article
- Prediction and Characterization of CYP3A4-mediated Metabolisms of Azole Fungicides: an Application of the Fused-grid Template* system.Food safety (Tokyo, Japan) · 2020Article
- Clobetasol Propionate Is a Heme-Mediated Selective Inhibitor of Human Cytochrome P450 3A5.Journal of medicinal chemistry · 2020Article
- Article
- Effects of CYP46A1 Inhibition on Long-Term-Depression in Hippocampal SlicesFrontiers in molecular neuroscience · 2020Article
- Cholesterol 24-Hydroxylation by CYP46A1: Benefits of Modulation for Brain Diseases.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2019Review
Corrections and comments
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Authors and funding
4 authors at 2 institutions in 1 country.
Funding
Abstract
Although there are currently three generations of antifungal azoles on the market, even the third-generation agents show undesirable interactions with human cytochrome P450 (P450) enzymes. CYP46A1 is a cholesterol-metabolizing P450 in the brain that tightly binds a number of structurally distinct azoles. Previously, we determined the crystal structures of CYP46A1 in complex with voriconazole and clotrimazole, and in the present work we cocrystallized the P450 with posaconazole at 2.5 Å resolution. This long antifungal drug coordinates the P450 heme iron with the nitrogen atom of its terminal azole ring and adopts a linear configuration occupying the whole length of the substrate access channel and extending beyond the protein surface. Numerous drug-protein interactions determine the submicromolar Kd of posaconazole for CYP46A1. We compared the crystal structure of posaconazole-bound CYP46A1 with those of the P450 in complex with other drugs, including the antifungal voriconazole and clotrimazole. We also analyzed the accommodation of posaconazole in the active site of the target enzymes, CYPs 51, from several pathogenic species. These and the solution studies with different marketed azoles, collectively, allowed us to identify the determinants of tight azole binding to CYP46A1 and generate an overall picture of azole binding to this important P450. The data obtained suggest that development of CYP51-specific antifungal agents will continue to be a challenge. Therefore, structural understanding of the azole binding not only to CYPs 51 from the pathogenic species but also to different human P450s is required to deal efficiently with this challenge.
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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.