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2019 Fiscal Year Final Research Report

Interdisciplinary medicinal chemistry: Synthesis and biological evaluation

Research Project

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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
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
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.

Free Research Field

創薬化学

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。

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Published: 2021-02-19  

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