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  1. 125 国際健康開発研究科・熱帯医学・グローバルヘルス研究科 = School of Tropical Medicine and Global Health
  2. 125 学術雑誌論文 = Articles in academic journal

The Open Form Inducer Approach for Structure-Based Drug Design

http://hdl.handle.net/10069/37359
http://hdl.handle.net/10069/37359
56f435b8-d1d8-4a1f-bcad-02b635b696b4
名前 / ファイル ライセンス アクション
PLoS11_167078.pdf PLoS11_167078.pdf (3.0 MB)
Item type 学術雑誌論文 / Journal Article(1)
公開日 2017-05-25
タイトル
タイトル The Open Form Inducer Approach for Structure-Based Drug Design
言語
言語 eng
資源タイプ
資源タイプ識別子 http://purl.org/coar/resource_type/c_6501
資源タイプ journal article
著者 Inaoka, Daniel Ken

× Inaoka, Daniel Ken

WEKO 10044

Inaoka, Daniel Ken

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Iida, Maiko

× Iida, Maiko

WEKO 10045

Iida, Maiko

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Tabuchi, Toshiyuki

× Tabuchi, Toshiyuki

WEKO 10046

Tabuchi, Toshiyuki

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Honma, Teruki

× Honma, Teruki

WEKO 10047

Honma, Teruki

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Lee, Nayoung

× Lee, Nayoung

WEKO 10048

Lee, Nayoung

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Hashimoto, Satoshi

× Hashimoto, Satoshi

WEKO 10049

Hashimoto, Satoshi

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Matsuoka, Shigeru

× Matsuoka, Shigeru

WEKO 10050

Matsuoka, Shigeru

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Kuranaga, Takefumi

× Kuranaga, Takefumi

WEKO 10051

Kuranaga, Takefumi

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Sato, Kazuhito

× Sato, Kazuhito

WEKO 10052

Sato, Kazuhito

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Shiba, Tomoo

× Shiba, Tomoo

WEKO 10053

Shiba, Tomoo

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Sakamoto, Kimitoshi

× Sakamoto, Kimitoshi

WEKO 10054

Sakamoto, Kimitoshi

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Balogun, Emmanuel Oluwadare

× Balogun, Emmanuel Oluwadare

WEKO 10055

Balogun, Emmanuel Oluwadare

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Suzuki, Shigeo

× Suzuki, Shigeo

WEKO 10056

Suzuki, Shigeo

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Nara, Takeshi

× Nara, Takeshi

WEKO 10057

Nara, Takeshi

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Rocha, Josmar Rodrigues da

× Rocha, Josmar Rodrigues da

WEKO 10058

Rocha, Josmar Rodrigues da

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Montanari, Carlos Alberto

× Montanari, Carlos Alberto

WEKO 10059

Montanari, Carlos Alberto

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Tanaka, Akiko

× Tanaka, Akiko

WEKO 10060

Tanaka, Akiko

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Inoue, Masayuki

× Inoue, Masayuki

WEKO 10061

Inoue, Masayuki

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Kita, Kiyoshi

× Kita, Kiyoshi

WEKO 10062

Kita, Kiyoshi

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Harada, Shigeharu

× Harada, Shigeharu

WEKO 10063

Harada, Shigeharu

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抄録
内容記述タイプ Abstract
内容記述 Many open form (OF) structures of drug targets were obtained a posteriori by analysis of cocrystals with inhibitors. Therefore, obtaining the OF structure of a drug target a priori will accelerate development of potent inhibitors. In addition to its small active site, Trypanosoma cruzi dihydroorotate dehydrogenase (TcDHODH) is fully functional in its monomeric form, making drug design approaches targeting the active site and protein-protein interactions unrealistic. Therefore, a novel a priori approach was developed to determination the TcDHODH active site in OF. This approach consists of generating an "OF inducer" (predicted in silico) to bind the target and cause steric repulsion with flexible regions proximal to the active site that force it open. We provide the first proof-of-concept of this approach by predicting and crystallizing TcDHODH in complex with an OF inducer, thereby obtaining the OF a priori with its subsequent use in designing potent and selective inhibitors. Fourteen cocrystal structures of TcDHODH with the designed inhibitors are presented herein. This approach has potential to encourage drug design against diseases where the molecular targets are such difficult proteins possessing small AS volume. This approach can be extended to study open/close conformation of proteins in general, the identification of allosteric pockets and inhibitors for other drug targets where conventional drug design approaches are not applicable, as well as the effective exploitation of the increasing number of protein structures deposited in Protein Data Bank.
書誌情報 PLOS ONE

巻 11, 号 11, p. e0167078, 発行日 2016-11-28
出版者
出版者 Public Library of Science
EISSN
収録物識別子タイプ ISSN
収録物識別子 19326203
DOI
関連タイプ isIdenticalTo
識別子タイプ DOI
関連識別子 10.1371/journal.pone.0167078
権利
権利情報 c 2016 Inaoka et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
著者版フラグ
出版タイプ VoR
出版タイプResource http://purl.org/coar/version/c_970fb48d4fbd8a85
引用
内容記述タイプ Other
内容記述 PLOS ONE, 11(11), e0167078; 2016
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