2018 Fiscal Year Final Research Report
In silico, in vitro, X-ray crystallography, and integrated strategies for discovering spermidine synthase inhibitors for Chagas disease
| Project/Area Number |
15H02776
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Life / Health / Medical informatics
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| Research Institution | Tokyo Institute of Technology |
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Principal Investigator |
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| Co-Investigator(Kenkyū-buntansha) |
秋山 泰 東京工業大学, 情報理工学院, 教授 (30243091)
平山 謙二 長崎大学, 熱帯医学研究所, 教授 (60189868)
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| Research Collaborator |
Kita Kiyoshi
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| Project Period (FY) |
2015-04-01 – 2019-03-31
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| Keywords | スマート創薬 / ケモインフォマティクス / バイオインフォマティクス / IT創薬 |
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| Outline of Final Research Achievements |
Chagas disease results from infection by Trypanosoma cruzi and is a neglected tropical disease (NTD). Although some treatment drugs are available, their use is associated with severe problems, including adverse effects and limited effectiveness during the chronic disease phase. To develop a novel anti-Chagas drug, we virtually screened 4.8 million small molecules against spermidine synthase (SpdSyn) as the target protein using our super computer “TSUBAME2.5” and conducted in vitro enzyme assays to determine the half-maximal inhibitory concentration values. We identified four hit compounds that inhibit T. cruzi SpdSyn (TcSpdSyn) by in silico and in vitro screening. We also determined the TcSpdSyn-hit compound complex structure using X-ray crystallography, which shows that the hit compound binds to the putrescine-binding site and interacts with Asp171 through a salt bridge.
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| Free Research Field |
スマート創薬
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| Academic Significance and Societal Importance of the Research Achievements |
WHOが焦点を当てているNTDsの17の疾患群は、世界で10億人以上が感染しているとされているが、未だ安価で安全な治療薬を入手できない為に、人々の生命を脅かす健康問題に留まらず、経済活動の足かせ・貧困の原因ともなっている。2015年に採択された持続可能な開発目標（SDGs）における目標3においてNTDsの根絶が掲げられており、本研究はシャーガス病治療薬候補探索を行うことで直接的にSDGsへの貢献っているほか、疾病に関わる標的遺伝子、標的蛋白質と薬化合物候補との相互作用様式、化合物のスクリーニングの実験結果等の公開など、NTDsの根絶に向けての基礎データの開示も積極的に行った。
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