2014 Fiscal Year Final Research Report
In silico drug design of SHIP2 inhibitor as a novel therapeutic agent for diabetes.
| 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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| 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 |
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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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| Free Research Field |
生物物理化学
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