| Project/Area Number |
24590058
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Research Field |
Physical pharmacy
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| Research Institution | Showa University (2013-2014)
Kitasato University (2012) |
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Principal Investigator |
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| Co-Investigator(Renkei-kenkyūsha) |
HIRONO Shuichi 北里大学, 薬学部, 教授 (30146328)
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| Project Period (FY) |
2012-04-01 – 2015-03-31
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| Project Status |
Completed (Fiscal Year 2014)
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| Budget Amount *help |
¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000)
Fiscal Year 2014: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2013: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2012: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
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| Keywords | 分子設計 / ドッキング計算 / 結合自由エネルギー / SHIP2 / 阻害剤 / 糖尿病 / インスリン / SBDD / ドラッグデザイン / 分子ドッキング計算 / 結合自由エネルギー計算 / 分子動力学シミュレーション |
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| Outline of Final Research Achievements |
SH2 domain-containing inositol 5’-phosphatase 2 (SHIP2) plays as an endogenous negative regulator of insulin signaling. Therefore, SHIP2 is considered to have great potential as a drug target for treating obesity and type 2 diabetes. We recently identified a novel SHIP2 inhibitor, N-[4-(4-chlorobenzyloxy)pyridin-2-yl]-2-(2,6-difluorophenyl)acetamide (CPDA). The binding mode of CPDA with SHIP2 was first investigated based on molecular docking calculation. CPDA was suggested to form a total of four hydrogen bonds with L538, K541, S564, and R571 of SHIP2. Aromatic rings of CPDA were also found to form hydrophobic interactions with side alkyl chains of T532, I534, L538, K541, T563, and R571. We next designed derivatives of CPDA based on binding free energy calculation. Derivatives with an additional monosaccharide such as galactose were expected to possess more potent inhibitory activity against SHIP2.
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