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Interdisciplinary medicinal chemistry: Synthesis and biological evaluation

Research Project

Project/Area Number 17K17750
Research Category

Grant-in-Aid for Young Scientists (B)

Allocation TypeMulti-year Fund
Research Field Drug development chemistry
Chemical pharmacy
Research InstitutionKyushu University

Principal Investigator

Tomohara Keisuke  九州大学, 基幹教育院, 助教 (40711677)

Project Period (FY) 2017-04-01 – 2020-03-31
Project Status Completed (Fiscal Year 2019)
Budget Amount *help
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2019: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Keywords多成分系の分子変換 / 天然物様化合物 / ジメチルスルホキシド / 摂動効果 / 非特異的阻害 / 酵素阻害剤 / DMSO / 摂動 / 非特異的結合 / 多成分系 / 非特異的酵素阻害剤 / DMSO摂動効果 / 学際的創薬化学 / 分子間相互作用解析
Outline of Final Research Achievements

The present study developed and established a novel DMSO-perturbing assay to identify promiscuous enzyme inhibitors. The assay successfully identified nonspecific binding inhibitors of hyaluronidase, β-lactamase, α-chymotrypsin, and aldose reductase, typically by the attenuation of inhibitory activity by the influence of DMSO-addition. This attenuation would be attributed to the nonspecific binding property of inhibitors toward both productive and nonproductive (nondenatured) states of enzymes in perturbation solution. This working hypothesis was supported by spectroscopic analyses of enzyme conformations as well as kinetic analyses. Overall, these results provided a novel concept of the DMSO-perturbing assay. Furthermore, we have discovered novel inhibitors of aldose reductase from chemically-engineered extracts of natural products.

Academic Significance and Societal Importance of the Research Achievements

創薬シーズの探索研究においては、標的タンパク質のリガンド結合部位に対して真に特異的に結合する新規シーズを創製することが重要である。本研究では、新規シーズ分子の新規供給法を開発するとともに、酵素阻害剤の酵素活性部位特異性を評価するための新規手法としてのDMSO摂動法を開発した。DMSO摂動法の学術的意義は、主としてタンパク質の構造解析に用いられる“摂動”の概念を、タンパク質と有機分子の分子間結合様式の解析研究に初めて適用した点にある。DMSO摂動法は、関連する既知法とは異なる作動機構を有するため、既知法を補完する代替法として広範な評価系への利用が見込まれる。

Report

(4 results)
  • 2019 Annual Research Report   Final Research Report ( PDF )
  • 2018 Research-status Report
  • 2017 Research-status Report
  • Research Products

    (13 results)

All 2020 2019 2018 2017

All Journal Article (4 results) (of which Peer Reviewed: 4 results) Presentation (9 results) (of which Int'l Joint Research: 2 results,  Invited: 1 results)

  • [Journal Article] Early identification of promiscuous attributes of aldose reductase inhibitors using a DMSO-perturbation assay2020

    • Author(s)
      Keisuke Tomohara, Naoto Hasegawa, Isao Adachi, Yoshikazu Horino, Takeru Nose.
    • Journal Title

      Bioorganic & Medicinal Chemistry Letters

      Volume: 30 Issue: 2 Pages: 126815-126815

    • DOI

      10.1016/j.bmcl.2019.126815

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] DMSO-perturbing assay for identifying promiscuous enzyme inhibitors2019

    • Author(s)
      Keisuke Tomohara, Isao Adachi, Yoshikazu Horino, Hitoshi Kesamaru, Hitoshi Abe, Keitaro Suyama, Takeru Nose.
    • Journal Title

      ACS Medicinal Chemistry Letters

      Volume: 10 Issue: 6 Pages: 923-928

    • DOI

      10.1021/acsmedchemlett.9b00093

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Multiple production of α,α-disubstituted amino acid derivatives through direct chemical derivatization of natural plant extracts: An apparently difficult but successful route2017

    • Author(s)
      Tomohara Keisuke、Ito Tomohiro、Furusawa Kota、Hasegawa Naoto、Tsuge Kiyoshi、Kato Atsushi、Adachi Isao
    • Journal Title

      Tetrahedron Letters

      Volume: 58 Issue: 32 Pages: 3143-3147

    • DOI

      10.1016/j.tetlet.2017.06.087

    • Related Report
      2017 Research-status Report
    • Peer Reviewed
  • [Journal Article] Controllable Stereoselective Synthesis of (Z)- and (E)-Homoallylic Alcohols Using a Palladium-Catalyzed Three-Component Reaction2017

    • Author(s)
      Horino Yoshikazu、Sugata Miki、Mutsuura Itaru、Tomohara Keisuke、Abe Hitoshi
    • Journal Title

      Organic Letters

      Volume: 19 Issue: 21 Pages: 5968-5971

    • DOI

      10.1021/acs.orglett.7b02979

    • Related Report
      2017 Research-status Report
    • Peer Reviewed
  • [Presentation] 溶媒摂動効果を利用した酵素阻害剤の特異性評価2019

    • Author(s)
      大橋奈央、友原啓介、野瀬健
    • Organizer
      第36回日本薬学会九州支部大会
    • Related Report
      2019 Annual Research Report
  • [Presentation] 溶媒摂動効果を利用した初期スクリーニングヒットのバリデーション2019

    • Author(s)
      友原啓介、大橋奈央、栗木暖佳、巣山慶太郎、野瀬健
    • Organizer
      第37回メディシナルケミストリーシンポジウム
    • Related Report
      2019 Annual Research Report
  • [Presentation] Development of liposome-like nanostructures composed of short amphiphilic elastin-like peptides2019

    • Author(s)
      Naoki Sakamoto, Daiki Tatsubo, Keiji Sato, Keisuke Tomohara, Keitaro Suyama, Iori Maeda, Takeru Nose.
    • Organizer
      第56回ペプチド討論会
    • Related Report
      2019 Annual Research Report
  • [Presentation] DMSO摂動法を用いたアルドースレダクターゼ阻害剤の活性部位特異性評価2019

    • Author(s)
      友原啓介、長谷川直人、足立伊佐雄、野瀬健
    • Organizer
      日本薬学会第139年会
    • Related Report
      2018 Research-status Report
  • [Presentation] DMSO添加条件下における酵素阻害剤の活性部位特異性評価2018

    • Author(s)
      友原啓介、足立伊佐雄、袈裟丸仁志、野瀬健
    • Organizer
      平成30年度日本生化学会九州支部例会
    • Related Report
      2018 Research-status Report
  • [Presentation] DMSO-perturbing assay for identifying promiscuous enzyme inhibitors.2018

    • Author(s)
      Keisuke Tomohara
    • Organizer
      The Third International Symposium on Toyama-Asia-Africa Pharmaceutical Network
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research / Invited
  • [Presentation] Mechanistic Characterization of alpha-Chymotrypsin Inhibitors by DMSO-Perturbing Assay2018

    • Author(s)
      Keisuke Tomohara, Isao Adachi, Hitoshi Kesamaru, Takeru Nose
    • Organizer
      10th International Peptide Symposium
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research
  • [Presentation] DMSO摂動効果を利用した酵素阻害剤の活性部位特異性評価2018

    • Author(s)
      友原啓介,袈裟丸仁志,足立伊佐雄,巣山慶太郎,野瀬健
    • Organizer
      日本薬学会第138年会
    • Related Report
      2017 Research-status Report
  • [Presentation] DMSO摂動効果を利用した酵素阻害剤の分子間相互作用解析2017

    • Author(s)
      友原啓介,足立伊佐雄
    • Organizer
      創薬懇話会2017 in 加賀
    • Related Report
      2017 Research-status Report

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Published: 2017-04-28   Modified: 2021-02-19  

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