Interdisciplinary medicinal chemistry: Synthesis and biological evaluation
| Project/Area Number |
17K17750
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| Research Category |
Grant-in-Aid for Young Scientists (B)
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| Allocation Type | Multi-year Fund |
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| Research Field |
Drug development chemistry
Chemical pharmacy
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| Research Institution | Kyushu University |
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Principal Investigator |
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| Project Period (FY) |
2017-04-01 – 2020-03-31
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| Project Status |
Completed (Fiscal Year 2019)
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| 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)
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| 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 |
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| 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.
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| 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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Report
(4 results)
Research Products
(13 results)
