In Silico and Intuitive Predictions of CYP46A1 Inhibition by Marketed Drugs with Subsequent Enzyme Crystallization in Complex with Fluvoxamine
| العنوان: | In Silico and Intuitive Predictions of CYP46A1 Inhibition by Marketed Drugs with Subsequent Enzyme Crystallization in Complex with Fluvoxamine |
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| المؤلفون: | Natalia Mast, Irina A. Pikuleva, Jeffrey S. Wiseman, Matthew Clark, C. David Stout, Marlin Linger |
| المصدر: | Molecular Pharmacology. 82:824-834 |
| بيانات النشر: | American Society for Pharmacology & Experimental Therapeutics (ASPET), 2012. |
| سنة النشر: | 2012 |
| مصطلحات موضوعية: | Models, Molecular, Stereochemistry, Entropy, Quantitative Structure-Activity Relationship, Plasma protein binding, In Vitro Techniques, Crystallography, X-Ray, Hydroxylation, chemistry.chemical_compound, In vivo, Microsomes, Cholesterol 24-Hydroxylase, Animals, Humans, Computer Simulation, Protease Inhibitors, Heme, Enzyme Assays, Pharmacology, chemistry.chemical_classification, Molecular Structure, biology, Brain, Water, Cytochrome P450, Active site, Substrate (chemistry), Stereoisomerism, Articles, Antidepressive Agents, Recombinant Proteins, Cholesterol, Enzyme, chemistry, Fluvoxamine, Steroid Hydroxylases, biology.protein, Molecular Medicine, Cattle, Tranylcypromine, Crystallization, Protein Binding |
| الوصف: | Cytochrome P450 46A1 (cholesterol 24-hydroxylase) is an important brain enzyme that may be inhibited by structurally distinct pharmaceutical agents both in vitro and in vivo. To identify additional inhibitors of CYP46A1 among U.S. Food and Drug Administration-approved therapeutic agents, we used in silico and intuitive predictions and evaluated some of the predicted binders in the enzyme and spectral binding assays. We tested a total of 298 marketed drugs for the inhibition of CYP46A1-mediated cholesterol hydroxylation in vitro and found that 13 of them reduce CYP46A1 activity by >50%. Of these 13 inhibitors, 7 elicited a spectral response in CYP46A1 with apparent spectral K(d) values in a low micromolar range. One of the identified tight binders, the widely used antidepressant fluvoxamine, was cocrystallized with CYP46A1. The structure of this complex was determined at a 2.5 A resolution and revealed the details of drug binding to the CYP46A1 active site. The NH(2)-containing arm of the Y-shaped fluvoxamine coordinates the CYP46A1 heme iron, whereas the methoxy-containing arm points away from the heme group and has multiple hydrophobic interactions with aliphatic amino acid residues. The CF(3)-phenyl ring faces the entrance to the substrate access channel and has contacts with the aromatic side chains. The crystal structure suggests that only certain drug conformers can enter the P450 substrate access channel and reach the active site. Once inside the active site, the conformer probably further adjusts its configuration and elicits the movement of the protein side chains. |
| تدمد: | 1521-0111 0026-895X |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::d7438f463769f39f6248007042309e54 https://doi.org/10.1124/mol.112.080424 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....d7438f463769f39f6248007042309e54 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15210111 0026895X |
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