| ○種別 (必須): | □ | 学術論文 (審査論文)
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| ○言語 (必須): | □ | 英語
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| ○カテゴリ (推奨): |
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| ○学究種別 (推奨): |
| ○組織 (推奨): |
| ○著者 (必須): | 1. | (英) Sasahara Katsunori (日) (読)
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| 2. | (英) Mashima Akira (日) (読)
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| 3. | 吉田 達貞
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| 4. | 中馬 寛
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| ○題名 (必須): | □ | (英) Molecular dynamics and density functional studies on the metabolic selectivity of antipsychotic thioridazine by cytochrome P450 2D6: Connection with crystallographic and metabolic results (日)
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| ○副題 (任意): |
| ○要約 (任意): | □ | (英) CYP2D6, a cytochrome P450 isoform, significantly contributes to the metabolism of many clinically important drugs. Thioridazine (THD) is one of the phenothiazine-type antipsychotics, which exhibit dopamine D2 antagonistic activity. THD shows characteristic metabolic profiles compared to other phenothiazine-type antipsychotics such as chlorpromazine. The sulfur atom attached to the phenothiazine ring is preferentially oxidized mainly by CYP2D6, that is, the 2-sulfoxide is a major metabolite, and interestingly this metabolite shows more potent activity against dopamine D2 receptors than THD. On the other hand, the formation of this metabolite causes many serious problems for its clinical use. Wójcikowski et al. (Drug Metab. Dispos. 2006, 34, 471) reported a kinetic study of THD formed by CYP2D6. Recently, Wang et al. (J. Biol. Chem. 2012, 287, 10834 and J. Biol. Chem. 2015, 290, 5092) revealed the crystallographic structure of THD with CYP2D6. In the current study, the binding and reaction mechanisms at the atomic and electronic levels were computationally examined based on the assumption as to whether or not the different crystallographic binding poses correspond to the different metabolites. The binding and oxidative reaction steps in the whole metabolic process were investigated using molecular dynamics and density functional theory calculations, respectively. The current study demonstrated the essential importance of the orientation of the substrate in the reaction center of CYP2D6 for the metabolic reaction. (日)
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| ○キーワード (推奨): |
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| ○誌名 (必須): | □ | Bioorganic & Medicinal Chemistry ([Elsevier Science])
(pISSN: 0968-0896, eISSN: 1464-3391)
| ○ISSN (任意): | □ | 1464-3391
ISSN: 0968-0896
(pISSN: 0968-0896, eISSN: 1464-3391) Title: Bioorganic & medicinal chemistryTitle(ISO): Bioorg Med ChemPublisher: Elsevier Ltd (NLM Catalog)
(Scopus)
(CrossRef)
(Scopus information is found. [need login]) | [継承] |
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| ○巻 (必須): | □ | 23
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| ○号 (必須): | □ | 17
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| ○頁 (必須): | □ | 5459 5465
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| ○都市 (任意): |
| ○年月日 (必須): | □ | 西暦 2015年 9月 初日 (平成 27年 9月 初日)
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| ○URL (任意): |
| ○DOI (任意): | □ | 10.1016/j.bmc.2015.07.043 (→Scopusで検索)
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| ○PMID (任意): | □ | 26264841 (→Scopusで検索)
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| ○備考 (任意): | 1. | (英) Article.ELocationID: 10.1016/j.bmc.2015.07.043 (日)
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| 2. | (英) Article.ELocationID: S0968-0896(15)00627-6 (日)
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| 3. | (英) Article.PublicationTypeList.PublicationType: Journal Article (日)
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| 4. | (英) Article.PublicationTypeList.PublicationType: Research Support, Non-U.S. Gov't (日)
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| 5. | (英) KeywordList.Keyword: Activation energy (E(a)) (日)
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| 6. | (英) KeywordList.Keyword: Binding orientation (日)
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| 7. | (英) KeywordList.Keyword: Compound I (Cpd I) (日)
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| 8. | (英) KeywordList.Keyword: Crystallographic structure (日)
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| 9. | (英) KeywordList.Keyword: Cytochrome P450 2D6 (CYP2D6) (日)
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| 10. | (英) KeywordList.Keyword: Density functional theory (DFT) (日)
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| 11. | (英) KeywordList.Keyword: Mesoridazine (日)
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| 12. | (英) KeywordList.Keyword: Molecular dynamics (MD) (日)
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| 13. | (英) KeywordList.Keyword: Sites of metabolism (SOM) (日)
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| 14. | (英) KeywordList.Keyword: Sulforidazine (日)
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| 15. | (英) KeywordList.Keyword: Thioridazine (THD) (日)
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| 16. | (英) KeywordList.Keyword: Transition state (TS) (日)
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