| Project/Area Number |
18K19384
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| Research Category |
Grant-in-Aid for Challenging Research (Exploratory)
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| Allocation Type | Multi-year Fund |
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| Review Section |
Medium-sized Section 47:Pharmaceutical sciences and related fields
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| Research Institution | Hokkaido University |
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Principal Investigator |
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| Co-Investigator(Kenkyū-buntansha) |
薬師寺 文華 北海道大学, 薬学研究院, 講師 (40548476)
勝山 彬 北海道大学, 薬学研究院, 助教 (20824709)
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| Project Period (FY) |
2018-06-29 – 2021-03-31
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| Project Status |
Completed (Fiscal Year 2020)
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| Budget Amount *help |
¥6,240,000 (Direct Cost: ¥4,800,000、Indirect Cost: ¥1,440,000)
Fiscal Year 2020: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000)
Fiscal Year 2019: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
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| Keywords | 活性配座 / アトロプ異性 / 軸不斉 / アミド / チオアミド / アトロプ異性体 / 創薬化学 |
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| Outline of Final Research Achievements |
First, an indomethacin derivative having a substituent at the ortho positions of the benzene ring was synthesized and mixed with various proteins at 37 ° C. for 24 hours. As a result, a slight asymmetric amplification was observed when catalase was used. Next, we focused on the fact that the benzamide structure, which is a structure widely found in drugs, has two axial asymmetry of C-C bond and C-N bond, and investigated the properties of bond rotation. As a result, it was found that the type of substituent at the ortho position of the benzene ring shows the slow interconversion property characteristic of the atropisomer at a wide range of substituents, although the rotational speeds of both axes are slightly changed. Furthermore, this property was applied to enzyme inhibitors such as WDR5 inhibitors and HDAC inhibitors.
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| Academic Significance and Societal Importance of the Research Achievements |
本研究は従来の活性配座探索法の問題点を一挙に解決する極めて独創的な研究である。本法で用いる化合物の合成は極めて簡単で各種ジアステレオマーの合成をする必要がないこと、活性配座探索プロセスが迅速かつ簡便であること、既存のX線結晶構造解析法が利用できない標的分子に対しても化合物の活性配座を推測できること等の特徴を持ち、既存の手法と比較して圧倒的な優位性を有する。本研究の達成により得られる活性配座は疾患の種類によらず、新薬創製を多方面で支援できるという大きな意義を有する。本研究で対象とする化合物の化学構造は、創薬リード化合物の新しいコア構造としての可能性も秘めており新薬リードの創製に大きく貢献できる。
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