Influence of structural flexibility of drug metabolizing enzyme on ligand recognition
| Project/Area Number |
17K08257
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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 | Meijo University |
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Principal Investigator |
Oda Akifumi 名城大学, 薬学部, 教授 (50433511)
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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 |
¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000)
Fiscal Year 2019: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2018: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2017: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
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| Keywords | 薬物代謝酵素 / 分子シミュレーション / 遺伝多型 / タンパク質構造柔軟性 / 酵素 / 薬学 |
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| Outline of Final Research Achievements |
In this study, static and dynamic structures of drug metabolizing enzymes, such as cytochrome P450 (CYP), dihydropyrimidinase and carboxylesterase, were elucidated by using computer simulations. For these enzymes, several mutants were investigated. The computational results suggest that the structural flexibility plays an important role in the structures of ligand binding pocket and the cofactor binding, and it influences on the enzymatic activity. The structural flexibilities were influenced by only one residue mutation. Even in the CYP family enzymes, dynamic structures of the different molecules were largely different.
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| Academic Significance and Societal Importance of the Research Achievements |
医薬品は体内に入った後、適切に出て行かなければならない。その際に機能するのが薬物代謝酵素であるが、遺伝多型によってその機能には個人差が生じやすい。薬物代謝における個人差は薬効および副作用の個人差に直結するため、遺伝多型が薬物代謝酵素に与える影響を明確にすることは薬物治療の個人差を解明する上で極めて重要である。本研究ではそのような薬物代謝酵素の機能の個人差を分子構造のレベルから解明する上で有用である。特に静的構造が似通っているように見える分子においてもその動的構造が異なることをシミュレーションによって明らかにしており、個人差の影響を最小化するための創薬へとつながりうる成果を得た。
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Report
(4 results)
Research Products
(71 results)
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[Presentation] Functional characterization of 11 allelic variants of CYP2C9 identified in 3554 Japanese individuals2019
Author(s)
Kumondai M, Ito A, Saito T, Saito S, Yasuda J, Nagasaki M, Kinoshita K, Yamamoto M, Oda A, Hirasawa N, Hiratsuka M
Organizer
International Conferences on Cytochrome P450
Related Report
Int'l Joint Research
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