ArticleThe Journal of biological chemistry2013
Binding of a cyano- and fluoro-containing drug bicalutamide to cytochrome P450 46A1: unusual features and spectral response.
Article in The Journal of biological chemistry, 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 20 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
20 citing papers in PubMed, 45 citations in OpenAlex.
- N-substituted-4-(pyridin-4-ylalkyl)piperazine-1-carboxamides and related compounds as Leishmania CYP51 and CYP5122A1 inhibitors.Bioorganic & medicinal chemistry · 2024Article
- CYP5122A1 encodes an essential sterol C4-methyl oxidase in Leishmania donovani and determines the antileishmanial activity of antifungal azoles.Nature communications · 2024Article
- 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
- Cholesterol Hydroxylating Cytochrome P450 46A1: From Mechanisms of Action to Clinical Applications.Frontiers in aging neuroscience · 2021Review
- Soticlestat, a novel cholesterol 24-hydroxylase inhibitor shows a therapeutic potential for neural hyperexcitation in mice.Scientific reports · 2020Article
- Conformational selection is present in ligand binding to cytochrome P450 19A1 lipoprotein nanodiscs.Journal of inorganic biochemistry · 2020Article
- In Vitro Activation of Cytochrome P450 46A1 (CYP46A1) by Efavirenz-Related Compounds.Journal of medicinal chemistry · 2020Article
- Human Cytochrome P450 1A1 Adapts Active Site for Atypical Nonplanar Substrate.Drug metabolism and disposition: the biological fate of chemicals · 2020Article
- Cholesterol 24-Hydroxylation by CYP46A1: Benefits of Modulation for Brain Diseases.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2019Review
- Cholesterol-metabolizing enzyme cytochrome P450 46A1 as a pharmacologic target for Alzheimer's disease.Neuropharmacology · 2017Article
- Article
- Intersection of the Roles of Cytochrome P450 Enzymes with Xenobiotic and Endogenous Substrates: Relevance to Toxicity and Drug Interactions.Chemical research in toxicology · 2017Article
- Mapping of the Allosteric Site in Cholesterol Hydroxylase CYP46A1 for Efavirenz, a Drug That Stimulates Enzyme Activity.The Journal of biological chemistry · 2016Article
- Cholesterol hydroperoxides as substrates for cholesterol-metabolizing cytochrome P450 enzymes and alternative sources of 25-hydroxycholesterol and other oxysterols.Angewandte Chemie (International ed. in English) · 2015Article
- Marketed Drugs Can Inhibit Cytochrome P450 27A1, a Potential New Target for Breast Cancer Adjuvant Therapy.Molecular pharmacology · 2015Article
- Survey of Human Oxidoreductases and Cytochrome P450 Enzymes Involved in the Metabolism of Xenobiotic and Natural Chemicals.Chemical research in toxicology · 2015Review
- Pharmacologic stimulation of cytochrome P450 46A1 and cerebral cholesterol turnover in mice.The Journal of biological chemistry · 2014Article
- Antifungal Azoles: Structural Insights into Undesired Tight Binding to Cholesterol-Metabolizing CYP46A1.Molecular pharmacology · 2013Article
- Kinetics of cytochrome P450 3A4 inhibition by heterocyclic drugs defines a general sequential multistep binding process.The Journal of biological chemistryArticle
Corrections and comments
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Authors and funding
4 authors at 2 institutions in 1 country.
Funding
Abstract
Cytochrome P450 46A1 (CYP46A1) is the cholesterol 24-hydroxylase initiating the major pathways of cholesterol removal from the brain, and bicalutamide (BIC) is a drug of choice for the treatment of progressive androgen-dependent prostate cancer. We evaluated the interactions of BIC with CYP46A1 by x-ray crystallography and by conducting solution and mutagenesis studies. Because BIC is administered to patients as a racemic mixture of the S and R isomers, we studied all three, racemic BIC as well as the S and R isomers. Co-crystallization of CYP46A1 with racemic BIC led to structure determinations at 2.1 Å resolution with the drug complexes exhibiting novel properties. Both BIC isomers bind to the CYP46A1 active site in very similar single orientation and adopt an energetically unfavorable folded conformation. This folded BIC conformation is correlated with drug-induced localized shifts of amino acid side chains in CYP46A1 and unusual interactions in the CYP46A1-BIC complex. One of these interactions involves a water molecule that is coordinated to the P450 heme iron and also hydrogen-bonded to the BIC nitrile. Due to polarization of the water in this environment, the heme elicits previously unreported types of P450 spectral responses. We also observed that access to the P450 active site was affected by differential recognition of S versus R isomers at the CYP46A1 surface arising from BIC conformational polymorphism.
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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.