2020 Fiscal Year Final Research Report

Development of a quick and simple search method for active conformations with amplification and memory of active conformations as the key concept

Research Project

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Project/Area Number	18K19384
Research Category	Grant-in-Aid for Challenging Research (Exploratory)
Allocation Type	Multi-year Fund
Review Section	Medium-sized Section 47:Pharmaceutical sciences and related fields
Research Institution	Hokkaido University
Principal Investigator	Ichikawa Satoshi 北海道大学, 薬学研究院, 教授 (60333621)
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)
Project Period (FY)	2018-06-29 – 2021-03-31
Keywords	活性配座 / アトロプ異性 / 軸不斉
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.
Free Research Field	創薬化学
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。