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Mechanism of substrate recognition by cytochrome p450s and application to in silico prediction system of metabolites of drug candidates

Research Project

Project/Area Number 22510229
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Living organism molecular science
Research InstitutionKyoto University

Principal Investigator

AKAMATSU Miki  京都大学, 大学院・農学研究科, 准教授 (70183134)

Co-Investigator(Kenkyū-buntansha) SAKAKI Toshiyuki  富山県立大学, 工学部, 教授 (70293909)
IKUSHIRO Shinichi  富山県立大学, 工学部, 准教授 (50244679)
Project Period (FY) 2010 – 2012
Project Status Completed (Fiscal Year 2012)
Budget Amount *help
¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2012: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2011: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2010: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Keywords代謝酵素 / CYP / ケミカルゲノミクス / 基質認識 / 代謝物予測システム / 構造活性相関 / ケミカル・ゲノミクス
Research Abstract

To clarify the substrate recognition mechanism, we identified the metabolite structures of an insecticide, tebufenozide, as a model compound, and other compounds by major human CYP isozymes: CYP3A4, 2C19, 1A2, 2C9, 2D6 and 2E1, which are used as indicators of drug development. Then, docking simulation and hydrogen-abstraction energy calculation have been carried out to predict metabolites of the compounds. It was clarified that these methods were useful for the in silico prediction system of drug candidates.

Report

(4 results)
  • 2012 Annual Research Report   Final Research Report ( PDF )
  • 2011 Annual Research Report
  • 2010 Annual Research Report
  • Research Products

    (30 results)

All 2012 2011 2010 Other

All Journal Article (5 results) (of which Peer Reviewed: 5 results) Presentation (22 results) Remarks (3 results)

  • [Journal Article] Human cytochrome P450-dependent differential metabolism among three 2α-substituted-1α,25-dihydroxyvitamin D(3) analogs2012

    • Author(s)
      Yasuda, K, Ikushiro, S, Sakaki, T
    • Journal Title

      J. Steroid Biochem. Mol. Biol

      Volume: 133 Pages: 84-92

    • DOI

      10.1016/j.jsbmb.2012.09.006

    • Related Report
      2012 Annual Research Report 2012 Final Research Report
    • Peer Reviewed
  • [Journal Article] Structural basis of species differences between human and experimental animal CYP1A1s in metabolism of 3,3`,4,4`2011

    • Author(s)
      Yamazaki K, Sakaki T
    • Journal Title

      5-pentachlorobiphenyl,Journal of Biochemistry

      Volume: 149 Pages: 487-494

    • Related Report
      2012 Final Research Report
    • Peer Reviewed
  • [Journal Article] Metabolism of the c-Fos/Activator Protein-1 Inhibitor T-5224 by Multiple Human UDP-Glucuronosyltransferase Isoforms2011

    • Author(s)
      Uchihashi, S.,Ikushiro, S.,Sakaki, T.
    • Journal Title

      Drug Metabolism and Disposition

      Volume: 39 Issue: 5 Pages: 803-813

    • DOI

      10.1124/dmd.110.037952

    • Related Report
      2012 Final Research Report 2011 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Structural basis of species differences between human and experimental animal CYPlAls in metabolism of 3,3', 4,4', 5-pentachlorobiphenyl2011

    • Author(s)
      Yaraazaki K, Sakaki T, 他8名
    • Journal Title

      Journal of Biochemistry

      Volume: 149 Issue: 4 Pages: 487-494

    • DOI

      10.1093/jb/mvr009

    • Related Report
      2011 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Metabolism of sesamin by cytochromes P450 in human liver microsomes2010

    • Author(s)
      Yasuda K, Ikushiro S, Kamakura M, Ohta M, and Sakaki T
    • Journal Title

      Drug Metabolism and Disposition

      Volume: 38 Pages: 2117-2123

    • Related Report
      2012 Final Research Report 2010 Annual Research Report
    • Peer Reviewed
  • [Presentation] ヒト主要P450分子種によるモデル化合物Tebufenozideの代謝物同定およびIn Silico予測2012

    • Author(s)
      矢川勝太,赤松美紀
    • Organizer
      第40回構造活性相関シンポジウム
    • Place of Presentation
      愛知,岡崎
    • Year and Date
      2012-11-29
    • Related Report
      2012 Final Research Report
  • [Presentation] Difference of Substrate Recognition Between Human CYP Isozymes Based on Metabolite Identification and In Silico Prediction2012

    • Author(s)
      Yagawa, M., Akamatsu, M
    • Organizer
      第9回薬物の分子設計と開発に関する日中合同シンポジウム
    • Place of Presentation
      中華人民共和国桂林市.
    • Year and Date
      2012-09-22
    • Related Report
      2012 Final Research Report
  • [Presentation] Difference of substrate recognition between human CYP3A4 and CYP2C19 based on metabolite identification and in silico prediction2012

    • Author(s)
      城谷直紀、榊利之、生城真一、赤松美紀
    • Organizer
      第18回ヨーロッパ構造活性相関シンポジウム
    • Place of Presentation
      ギリシャ、ロードス島,ロードスパレス国際コンベンションセンター.
    • Year and Date
      2012-09-20
    • Related Report
      2012 Final Research Report
  • [Presentation] 代謝・排泄に関する分子モデリング2012

    • Author(s)
      赤松美紀
    • Organizer
      第305回細胞工学研究会講演会(招待講演)
    • Place of Presentation
      島根,島根大学
    • Year and Date
      2012-01-20
    • Related Report
      2012 Final Research Report
  • [Presentation] 代謝・排泄に関する分子モデリング2012

    • Author(s)
      赤松美紀
    • Organizer
      第305回細胞工学研究会講演会
    • Place of Presentation
      島根、島根大学(招待講演)
    • Year and Date
      2012-01-20
    • Related Report
      2011 Annual Research Report
  • [Presentation] Difference of Substrate Recognition Between Human CYP Isozymes Based on Metabolite Identification and In Silico Prediction2012

    • Author(s)
      Yagawa, M., Akamatsu, M. 他7名( 赤松美紀)
    • Organizer
      第9回薬物の分子設計と開発に関する日中合同シンポジウム
    • Place of Presentation
      中華人民共和国桂林市
    • Related Report
      2012 Annual Research Report
  • [Presentation] ヒト主要P450分子種によるモデル化合物Tebufenozideの代謝物同定およびIn Silico予測2012

    • Author(s)
      矢川勝太,赤松美紀,他7名( 赤松美紀)
    • Organizer
      第40回構造活性相関シンポジウム
    • Place of Presentation
      愛知県岡崎市
    • Related Report
      2012 Annual Research Report
  • [Presentation] Identification and In Silico Prediction of Tebufenozide Metabolites by Major Human CYP Isozymes2012

    • Author(s)
      Yagawa, M., Akamatsu, M. 他7名( 赤松美紀)
    • Organizer
      チトクロムP450発見50周年記念シンポジウム
    • Place of Presentation
      福岡県福岡市
    • Related Report
      2012 Annual Research Report
  • [Presentation] Cytochrome P450 3A4 Alters the Affinity of UDP-glucuronosyltransferase 1A Isoforms toward UDP-glucuronic acid2012

    • Author(s)
      Kinoshita, K., Ikushiro, S. 他7名( 生城真一)
    • Organizer
      日本薬物動態学会第27回年会
    • Place of Presentation
      東京都
    • Related Report
      2012 Annual Research Report
  • [Presentation] セサミンおよびエピセサミンのヒト体内における代謝予測2011

    • Author(s)
      安田佳織、生城真一、榊利之
    • Organizer
      第84回日本生化学会大会
    • Place of Presentation
      京都,国立京都国際会館
    • Year and Date
      2011-09-21
    • Related Report
      2012 Final Research Report
  • [Presentation] セサミンおよびエピセサミンのヒト体内における代謝予測2011

    • Author(s)
      安田佳織、生城真一、榊利之, 他5名
    • Organizer
      第84回日本生化学会大会
    • Place of Presentation
      京都、国立京都国際会館
    • Year and Date
      2011-09-21
    • Related Report
      2011 Annual Research Report
  • [Presentation] ラットおよびヒトCYP1A1によるポリ塩化ビフェニルの代謝と3次元構造の比較2011

    • Author(s)
      薮未来、榊利之
    • Organizer
      第20回環境化学討論会
    • Place of Presentation
      熊本,熊本県立大学
    • Year and Date
      2011-07-16
    • Related Report
      2012 Final Research Report
  • [Presentation] ラットおよびヒトCYPlAlによるポリ塩化ビフェニルの代謝と3次元構造の比較2011

    • Author(s)
      薮未来、榊利之, 他9名
    • Organizer
      第20回環境化学討論会
    • Place of Presentation
      熊本、熊本県立大学
    • Year and Date
      2011-07-16
    • Related Report
      2011 Annual Research Report
  • [Presentation] ヒトCYP3A4およびCYP2C19のTebufenozide代謝における立体選択性の差異2011

    • Author(s)
      城谷直紀、榊利之、生城真一、赤松美紀
    • Organizer
      日本農薬学会第36回大会
    • Place of Presentation
      日本農薬学会第36回大会
    • Year and Date
      2011-03-17
    • Related Report
      2012 Final Research Report
  • [Presentation] ヒトCYP3A4およびCYP2C19のTebufenozide代謝における立体選択性の差異2011

    • Author(s)
      城谷直紀、榊利之、生城真一、赤松美紀, 他4名
    • Organizer
      日本農薬学会第36回大会
    • Place of Presentation
      東京、玉川大学
    • Year and Date
      2011-03-17
    • Related Report
      2010 Annual Research Report
  • [Presentation] ラットおよびヒトCYP1A1による3,3',4,4'-テトラクロロビフェニルの代謝能の比較2010

    • Author(s)
      薮未来、榊利之
    • Organizer
      日本分子生物学会・日本生化学会合同会議
    • Place of Presentation
      兵庫,神戸
    • Year and Date
      2010-12-08
    • Related Report
      2012 Final Research Report
  • [Presentation] ラットおよびヒトCYP1A1による3,3',4,4'-テトラクロロビフェニルの代謝能の比較2010

    • Author(s)
      薮未来、榊利之, 他7名
    • Organizer
      BMB2010(日本分子生物学会・日本生化学会合同会議)
    • Place of Presentation
      神戸、ポートアイランド
    • Year and Date
      2010-12-08
    • Related Report
      2010 Annual Research Report
  • [Presentation] 代謝物同定およびin silico予測を用いたCYP3A4とCYP2C19における基質認識機構の差異2010

    • Author(s)
      城谷直紀、榊利之、生城真一、赤松美紀
    • Organizer
      第38回構造活性相関シンポジウム
    • Place of Presentation
      徳島,徳島大学
    • Year and Date
      2010-10-30
    • Related Report
      2012 Final Research Report
  • [Presentation] 代謝物同定およびin silico予測を用いたCYP3A4とCYP2C19における基質認識機構の差異2010

    • Author(s)
      城谷直紀、榊利之、生城真一、赤松美紀, 他4名
    • Organizer
      第38回構造活性相関シンポジウム
    • Place of Presentation
      徳島、徳島大学
    • Year and Date
      2010-10-30
    • Related Report
      2010 Annual Research Report
  • [Presentation] Difference of substrate recognition between human CYP3A4 and CYP2C19 based onmetabolite identification and in silico prediction2010

    • Author(s)
      城谷直紀、榊利之、生城真一、赤松美紀, 他4名
    • Organizer
      第18回ヨーロッパ構造活性相関シンポジウム
    • Place of Presentation
      ギリシャ、ロードス島ロードスパレス国際コンベンションセンター
    • Year and Date
      2010-09-20
    • Related Report
      2010 Annual Research Report
  • [Presentation] ヒト代謝酵素CYP3A4とCYP2C19の基質認識機構における差異-Tebufenozideを例として2010

    • Author(s)
      城谷直紀、榊利之、生城真一、赤松美紀
    • Organizer
      日本農薬学会第35回大会
    • Place of Presentation
      札幌,北海道大学
    • Year and Date
      2010-05-29
    • Related Report
      2012 Final Research Report
  • [Presentation] ヒト代謝酵素CYP3A4とCYP2C19の基質認識機構における差異-Tebufenozideを例として-2010

    • Author(s)
      城谷直紀、榊利之、生城真一、赤松美紀, 他7名
    • Organizer
      日本農薬学会第35回大会
    • Place of Presentation
      札幌、北海道大学
    • Year and Date
      2010-05-29
    • Related Report
      2010 Annual Research Report
  • [Remarks] 研究内容についてのWebページ

    • URL

      http://www.fsao.kais.kyoto-u.ac.jp/cas/index.php?%E8%B5%A4%E6%9D%BE%E3%80%80%E7%BE%8E%E7%B4%80

    • Related Report
      2012 Final Research Report
  • [Remarks]

    • URL

      http://www.fsao.kais.kyoto-u.ac.jp/cas/index.php?%E8%B5%A4%E6%9D%BE%E3%80%80%E7%BE%8E%E7%B4%80

    • Related Report
      2011 Annual Research Report
  • [Remarks]

    • URL

      http://www.fsao.kais.kyoto-u.ac.jp/cas/index.php?%E8%B5%A4%E6%9D%BE%E3%80%80%E7%BE%8E%E7%B4%80

    • Related Report
      2010 Annual Research Report

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Published: 2010-08-23   Modified: 2019-07-29  

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