دورية أكاديمية
أعرض في EDS

Binding Modes and Metabolism of Caffeine.

التفاصيل البيبلوغرافية
العنوان: Binding Modes and Metabolism of Caffeine.
المؤلفون: Jandova Z; Institute of Molecular Modeling and Simulation , University of Natural Resources and Life Sciences, Vienna , 1180 Vienna , Austria., Gill SC, Lim NM, Mobley DL, Oostenbrink C; Institute of Molecular Modeling and Simulation , University of Natural Resources and Life Sciences, Vienna , 1180 Vienna , Austria.
المصدر: Chemical research in toxicology [Chem Res Toxicol] 2019 Jul 15; Vol. 32 (7), pp. 1374-1383. Date of Electronic Publication: 2019 Jun 11.
نوع المنشور: Journal Article; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: American Chemical Society Country of Publication: United States NLM ID: 8807448 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1520-5010 (Electronic) Linking ISSN: 0893228X NLM ISO Abbreviation: Chem Res Toxicol Subsets: MEDLINE
أسماء مطبوعة: Publication: Washington Dc : American Chemical Society
Original Publication: Washington, DC : American Chemical Society, c1988-
مواضيع طبية MeSH: Caffeine/*metabolism , Cytochrome P-450 CYP1A2/*metabolism, Caffeine/chemistry ; Catalytic Domain ; Cytochrome P-450 CYP1A2/chemistry ; Heme/chemistry ; Humans ; Ligands ; Models, Chemical ; Molecular Dynamics Simulation ; Monte Carlo Method ; Protein Binding
مستخلص: A correct estimate of ligand binding modes and a ratio of their occupancies is crucial for calculations of binding free energies. The newly developed method BLUES combines molecular dynamics with nonequilibrium candidate Monte Carlo. Nonequilibrium candidate Monte Carlo generates a plethora of possible binding modes and molecular dynamics enables the system to relax. We used BLUES to investigate binding modes of caffeine in the active site of its metabolizing enzyme Cytochrome P450 1A2 with the aim of elucidating metabolite-formation profiles at different concentrations. Because the activation energies of all sites of metabolism do not show a clear preference for one metabolite over the others, the orientations in the active site must play a key role. In simulations with caffeine located in a spacious pocket above the I-helix, it points N3 and N1 to the heme iron, whereas in simulations where caffeine is in close proximity to the heme N7 and C8 are preferably oriented toward the heme iron. We propose a mechanism where at low caffeine concentrations caffeine binds to the upper part of the active site, leading to formation of the main metabolite paraxanthine. On the other hand, at high concentrations two molecules are located in the active site, forcing one molecule into close proximity to the heme and yielding metabolites theophylline and trimethyluretic acid. Our results offer an explanation of previously published experimental results.
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معلومات مُعتمدة: W 1224 Austria FWF_ Austrian Science Fund FWF
المشرفين على المادة: 0 (Ligands)
3G6A5W338E (Caffeine)
42VZT0U6YR (Heme)
EC 1.14.14.1 (Cytochrome P-450 CYP1A2)
تواريخ الأحداث: Date Created: 20190528 Date Completed: 20200630 Latest Revision: 20220727
رمز التحديث: 20240628
مُعرف محوري في PubMed: PMC6635882
DOI: 10.1021/acs.chemrestox.9b00030
PMID: 31132250
قاعدة البيانات: MEDLINE
الوصف
تدمد:1520-5010
DOI:10.1021/acs.chemrestox.9b00030