Molecular modeling based design of pseudo-symmetric enzyme inhibitors
| Project/Area Number |
19790100
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| Research Category |
Grant-in-Aid for Young Scientists (B)
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| Allocation Type | Single-year Grants |
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| Research Field |
Drug development chemistry
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| Research Institution | Kyoto Pharmaceutical University |
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Principal Investigator |
HIDAKA Koushi Kyoto Pharmaceutical University, 薬学部, 助手 (30445960)
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| Project Period (FY) |
2007 – 2008
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| Project Status |
Completed (Fiscal Year 2008)
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| Budget Amount *help |
¥3,750,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥450,000)
Fiscal Year 2008: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
Fiscal Year 2007: ¥1,800,000 (Direct Cost: ¥1,800,000)
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| Keywords | 酵素阻害剤 / 擬似対称型 / 分子モデリング / 分子設計 / アスパラギン酸プロテアーゼ / HIVプロテアーゼ / プラスメプシン / ヒドロキシメチルカルボニル / 擬似対称型酵素阻害剤 / HMC-ヒドラジド |
|---|
| Research Abstract |
基質遷移状態を模倣した理想的なヒドロキシルメチルカルボニル(HMC)構造とヒドラジド構造を融合した「HMC-ヒドラジド」を組み込む擬似対称型化合物をデザインした。HIVプロテアーゼとの複合体の分子モデリングを構築し、実際にHMC-ヒドラジド化合物を合成して、強力なHIVプロテアーゼ阻害剤へと導いた。また、本デザイン手法をマラリア原虫プラスメプシンの阻害剤にも応用し、対称型酵素でないアスパラギン酸プロテアーゼの阻害剤にも適応可能であることを示した。
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Report
(3 results)
Research Products
(19 results)
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[Journal Article] Structure of HIV-1 protease incomplex with potent inhibitor KNI-272 determined by high resolution X-ray and neutron crystallography2009
Author(s)
Motoyasu Adachi, Takashi Ohhara, Kazuo Kurihara, Taro Tamada, Eijiro Honjo, Nobuo Okazaki, Shigeki Arai, Yoshinari Shoyama, Kaname Kimura, Hiroyoshi Matsumura, Shigeru Sugiyama, Hiroaki Adachi, Kazufumi Takano, Yusuke Mori, Koushi Hidaka, Tooru Kimura, Yoshio Hayashi, Yoshiaki Kiso, and Ryota Kuroki
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Journal Title
Proc. Natl. Acad. Sci. USA 106(12)
Pages: 4641-4646
Related Report
Peer Reviewed
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[Journal Article] Antimalarial activity enhancement in hydroxymethylcarbonyl (HMC) isostere-based dipeptidomimetics targeting malarial aspartic protease plasmepsin2008
Author(s)
Koushi Hidaka, Tooru Kimura, Adam J. Ruben, Tsuyoshi Uemura, Mami Kamiya, Aiko Kiso, Tetsuya Okamoto, Yumi Tsuchiya, Yoshio Hayashi, Ernesto Freire, and Yoshiaki Kiso
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Journal Title
Bioorg. Med. Chem. 16(23)
Pages: 10049-10060
Related Report
Peer Reviewed
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[Journal Article] Combination of Non-natural D-amino acid derivatives and allophenylnorstatine-dimethylthioproline scaffold in HIV protease inhibitors have high efficacy in mutant2008
Author(s)
Shingo Nakatani, Koushi Hidaka, Ei' ichi Ami, Koichiro Nakahara, Akihiko Sato, Jeffrey-Tri Nguyen, Yoshio Hamada, Yasuko Hori, Nobuyuki Ohnishi, Akinori Nagai, Tooru Kimura, Yoshio Hayashi, and Yoshiaki Kiso
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Journal Title
HIV. J. Med. Chem. 51(10)
Pages: 2992-3004
Related Report
Peer Reviewed
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[Presentation] HIV protease and malarial plasmepsin inhibitors with hydroxymethylcarbonyl isostere2007
Author(s)
Koushi Hidaka, Tooru Kimura, Yumi Tsuchiya, Mami Kamiya, Ernesto Freire, Ben M. Dunn, Yoshio Hayashi, Yoshiaki Kiso
Organizer
5th General Meeting of the International Proteolysis Society
Place of Presentation
Conference and Cultural Center, University of Patras, Patras, Greece
Related Report
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