In Vitro Activation of Cytochrome P450 46A1 (CYP46A1) by Efavirenz-Related Compounds
| العنوان: | In Vitro Activation of Cytochrome P450 46A1 (CYP46A1) by Efavirenz-Related Compounds |
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| المؤلفون: | Irina A. Pikuleva, F P Guengerich, Wilkey Cj, Peter Verwilst, Natalia Mast |
| المصدر: | J Med Chem |
| بيانات النشر: | American Chemical Society (ACS), 2019. |
| سنة النشر: | 2019 |
| مصطلحات موضوعية: | Cyclopropanes, Efavirenz, Protein Conformation, Allosteric regulation, Cytochrome P-450 CYP3A Inducers, In Vitro Techniques, Hydroxylation, 01 natural sciences, 03 medical and health sciences, chemistry.chemical_compound, immune system diseases, Catalytic Domain, parasitic diseases, Drug Discovery, Cholesterol 24-Hydroxylase, Humans, heterocyclic compounds, Cholesterol 24-hydroxylase, 030304 developmental biology, chemistry.chemical_classification, 0303 health sciences, biology, Cholesterol, virus diseases, Cytochrome P450, biochemical phenomena, metabolism, and nutrition, Benzoxazines, 0104 chemical sciences, 010404 medicinal & biomolecular chemistry, Enzyme, Pharmaceutical Preparations, chemistry, Biochemistry, Alkynes, biology.protein, Molecular Medicine, Allosteric Site |
| الوصف: | Cytochrome P450 46A1 (CYP46A1) is a central nervous system-specific enzyme, which catalyzes cholesterol 24-hydroxylation. Currently CYP46A1 is being evaluated in a clinical trial for activation by small doses of the anti-HIV drug efavirenz. Eight efavirenz-related compounds were investigated for CYP46A1 activation in vitro, induction of a CYP46A1 spectral response, spectral Kd values, interaction with the P450 allosteric sites, and a model of binding to the enzyme active site. We gained insight into structure-activity relationships of efavirenz for CYP46A1 activation and found that the investigated efavirenz primary metabolites are stronger and better activators of CYP46A1 than efavirenz. We also established that CYP46A1 is activated by racemates and that a conformational-selection mechanism is operative in CYP46A1. The results suggest structural modifications of efavirenz to further increase CYP46A1 activation without inhibition at high compound concentrations. It is possible that not only efavirenz but its metabolites activate CYP46A1 in vivo. ispartof: JOURNAL OF MEDICINAL CHEMISTRY vol:63 issue:12 pages:6477-6488 ispartof: location:United States status: published |
| وصف الملف: | Print-Electronic |
| تدمد: | 1520-4804 0022-2623 |
| DOI: | 10.1021/acs.jmedchem.9b01383 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::4638d56eb4c0f479fe518a95ad66f3f8 https://doi.org/10.1021/acs.jmedchem.9b01383 |
| Rights: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....4638d56eb4c0f479fe518a95ad66f3f8 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15204804 00222623 |
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| DOI: | 10.1021/acs.jmedchem.9b01383 |