Development of Novel Rational Drug Design Procedure and Its Applications to Anti-Influenza Drugs

2011 Fiscal Year Final Research Report

• Project/Area Number: 21590128
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Drug development chemistry
• Research Institution: Rikkyo University
• Principal Investigator: HIROAKI Tokiwa 立教大学, 理学部, 教授 (10221433)
• Project Period (FY): 2009 – 2011
• Keywords: 理論創薬 / インフルエンザ / フラグメント分子軌道法 / ONIOM法 / 部分構造最適化 / 核内受容体

Research Abstract

Recently, molecular simulations and in silico modelings of novel drugs with target protein based on rigorous quantum mechanical calculations are required. The fragment MO(FMO) method has been developed, enabling one to avoid the large computational cost. Our novel in silico modeling procedure based on the FMO method can be easily applied to typical biochemical and pharmaceutical topics. We have applied our novel in silico procedure to anti-iffluenza drugs, human parainfluenza inhibitors, anti-dengue virus inhibitors, and novel modulators for the nuclear receptors like the vitamin D and peroxisome proliferator-activated receptors.

Research Products

• [Journal Article] Modern Chemistry & Multisimulations that Support Current Drug Design (2012)
  • Author(s): Hiroaki Tokiwa
  • Journal Title: Yakuzakuzasshi Volume: 132(8)(in print)
• [Journal Article] Origin of inhibitory activity of 4-O-substituented sialic derivatives for human parainfluenza virus (2012)
  • Author(s): Yuji Itoh, Ayumi Sando, Kiyoshi Ikeda, Takashi Suzuki, and Hiroaki Tokiwa
  • Journal Title: Glyco. J Volume: 29 Pages: 231-237
• [Journal Article] Differential Expression and Function of Alternative Splicing Variants of Human Liver X Receptor α (2012)
  • Author(s): Kaori Endo-Umeda, S. Uno, K. Fujimori, Y. Naito, K. Saito, Kenji Yamagishi K. Jeong Hiroyuki Miyachi, Hiroaki Tokiwa, Sachiko Yamada, and Makoto Makishima
  • Journal Title: Mol. Pharm Volume: 81(6) Pages: 800-810
• [Journal Article] Activation of Adrenergic β Receptor by Free Fatty Acid Composition (2012)
  • Author(s): Yuka Nakano, Saki Kawase, Ayumi Sando, and Hiroaki Tokiwa
  • Journal Title: J. Comp. Chem. Jpn Pages: 2011-0014
  • DOI: DOI:10.2477/jccj
• [Journal Article] Structure-Activity Relationship of Novel Menaquinone-4 Analogues : Modification of the Side Chain Affects their Biological Activities (2012)
  • Author(s): Yoshitomo Suhara, Norika Hanada, T. Okitsu, Miho Sakai, M. Watanabe, Kimie Nakagawa, Akimori Wada, K. Takeda, K. Takahashi, Hiroaki Tokiwa, and Toshio Okano
  • Journal Title: J. Med. Chem Volume: 55 Pages: 1553-1558
• [Journal Article] Synthesis of New Vitamin K Analogues as Steroid and Xenobiotic Receptor(SXR) Agonists : Insights into the Biological Role of the Side Chain Part of Vitamin (2011)
  • Author(s): Yoshitomo Suhara, M. Watanabe, Sayaka Motoyoshi, Kimie Nakagawa, Akimori Wada, K. Takeda, T. Takahashi, Hiroaki Tokiwa, and Toshio Okano
  • Journal Title: J. Med. Chem Volume: 54 Pages: 4918-4922
• [Journal Article] Current Trends of Theoretical and Medicinal Chemistry (2011)
  • Author(s): Hiroaki Tokiwa
  • Journal Title: Yakugaku Zasshi Volume: 131(8) Pages: 1149-1150
• [Journal Article] Flexible Ligand Recognition of Peroxisome Proliferator-Activated Receptor-γ(PPARγ) (2010)
  • Author(s): Kenji Yagishi, Keiko Yamamoto, Yuji Mochizuki, Tatsuya Nakano, Ssachiko Yamada, and Hiroaki Tokiwa
  • Journal Title: Bioorg. Med. Chem. Lett Volume: 20(11) Pages: 3344-3347
• [Journal Article] Ligand-Dependent Conformation Change Reflects Steric Structure and Interactions of a Vitamin D Receptor/Ligand Complex : A Fragment Molecular Orbital Study (2010)
  • Author(s): Sayaka Motoyoshi, Kenji Yamagishi, Sachiko Yamada, and Hiroaki Tokiwa
  • Journal Title: J. Ster. Biochem. Mol. Bio Volume: 121 Pages: 56-59
• [Journal Article] Interactions Between 1α, 25(OH) 2D3 and Residues in the Ligand-Binding Pocket of the Vitamin D Receptor : A Correlated Fragment Molecular Orbital Study (2010)
  • Author(s): Kenji Yamagishi, Hiroaki Tokiwa, Makoto Makishima, and Sachiko Yamada
  • Journal Title: J. Ster. Biochem. Mol. Bio Volume: 121 Pages: 63-67
• [Journal Article] Ab initio based fragment molecular orbital studies of influenza viral hemagglutinin HA1 full domains with sialoside receptors (2009)
  • Author(s): Toshihiko Sawada, Tomohiro Hashimoto, Hiroaki Tokiwa, Tohru Suzuki, Hirofumi Nakano, Hideharu Ishida, Makoto Kiso, and Yasuo Suzuki
  • Journal Title: Avian Influenza and Human Health Special Issue Volume: 3(1) Pages: 133142
• [Presentation] Theoretical Interaction Analysis between Novel Inhibitors and Influenza Virus Neuraminidases using Fragment Molecular Orbital Method (2012)
  • Author(s): Miho Sakai, Takeshi Ishikawa, HIromune Ando, Hideharu Ishida, Makoto Kiso, Kazuo Kuwata, Yasuo Suzuki, and Hiroaki Tokiwa
  • Organizer: 8th AFMC International Medicinal Chemistry Symposium(AIMECS2011)
  • Place of Presentation: Tokyo, Japan
  • Year and Date: 20121129-1202
• [Presentation] All-Electronic Calculational Study of Novel Anti-Parainfluenza Drugs using Fragment Molecular Orbital Method (2012)
  • Author(s): Yuji Itoh, Kiyoshi Ikeda, Takashi Suzuki, and Hiroaki Tokiwa
  • Organizer: 8th AFMC International Medicinal Chemistry Symposium(AIMECS2011)
  • Place of Presentation: Tokyo, Japan
  • Year and Date: 20121129-1202
• [Presentation] 酵素は何をしているのか?新世紀の科学が解き明かす分子メカニズム,年会シンポジウム (2012)
  • Author(s): 阿部郁郎, 吉澤一成, 北浦和夫, 岡野登志夫, 常盤広明
  • Organizer: 第132回日本薬学会総会(シンポジウムオーガナイザー)
  • Place of Presentation: 札幌
  • Year and Date: 2012-03-30
• [Presentation] 遊離脂肪酸混合物によるβアドレナリン受容体の活性化 (2012)
  • Author(s): 中野佑香, 川瀬咲, 山藤歩, 常盤広明
  • Organizer: 第132回日本薬学会総会
  • Place of Presentation: 札幌
  • Year and Date: 2012-03-30
• [Presentation] ヒトパラインフルエンザウイルス(hPIV)感染症の新規治療薬開発研究 (2012)
  • Author(s): 伊東祐仁, 山藤歩, 池田潔、鈴木隆、常盤広明
  • Organizer: 第132回日本薬学会総会
  • Place of Presentation: 札幌
  • Year and Date: 2012-03-29
• [Presentation] デングウイルス感染症の新規薬剤の理論的分子設計 (2012)
  • Author(s): 山藤歩, 伊東祐仁, 池田潔, 左一八, 鈴木隆, 常盤広明
  • Organizer: 第132回日本薬学会総会
  • Place of Presentation: 札幌
  • Year and Date: 2012-03-29
• [Presentation] 新規in silico手法の開発およびその応用-スルファチド・インフルエンザHA複合体への適用- (2012)
  • Author(s): 山藤歩, 伊東祐仁, 池田潔, 高橋忠伸, 鈴木隆, 常盤広明
  • Organizer: 第132回日本薬学会総会
  • Place of Presentation: 札幌
  • Year and Date: 2012-03-29
• [Presentation] FMO法を用いた新規阻害剤とNeuraminidase(NA)との理論的相互作用解析 (2012)
  • Author(s): 酒井美帆, 石川岳志, 安藤弘宗, 石田秀治, 木曾真, 鈴木康夫, 常盤広明
  • Organizer: 第132回日本薬学会総会
  • Place of Presentation: 札幌
  • Year and Date: 2012-03-29
• [Presentation] ビタミンE同族体によるマウス胎仔神経幹細胞の増殖・分化調節 (2012)
  • Author(s): 岡野登志夫, 廣田佳久, 中川公恵, 須原義智, 元吉沙也加, 常盤広明
  • Organizer: 第23回ビタミンE研究会
  • Place of Presentation: 品川
  • Year and Date: 2012-01-28
• [Presentation] Theoretical Molecular Design of Novel Inhibitor for Dengue Virus Infection (2011)
  • Author(s): Ayumi Sando, Yuji Itoh, Kazuya Hidari, Kiyoshi Ikeda, Takashi Suzuki, and Hiroaki Tokiwa
  • Organizer: 34th Annual Meeting of Molecular Biology Society of Japan
  • Place of Presentation: Yokohama, Japan
  • Year and Date: 20111213-16
• [Presentation] Ab Initio Fragment Molecular Orbital Study of Nuclear Receptor Enhanceosome (2011)
  • Author(s): Norika Hanada, Takeshi Ishikawa, Hiraoyuki Miyachi, Kazuo Kuwata, and Hiroaki Tokiwa
  • Organizer: 34th Annual Meeting of Molecular Biology Society of Japan
  • Place of Presentation: Yokohama, Japan
  • Year and Date: 20111213-16
• [Presentation] First principles calculations of influenza neuraminidase mutants and anti-infl uenza drugs using ab initio fragment molecular orbital method (2011)
  • Author(s): Miho Sakai, Yasuo Suzuki, Y, and Hiroaki Tokiwa
  • Organizer: 21st International Symposium on Glycoconjuagates(Glyco21)
  • Place of Presentation: Vienna, Austria
  • Year and Date: 20110821-26
• [Presentation] First Principles Calculations of Novel Antiparainfluenza Drugs using Fragment Molecular Orbital Method (2011)
  • Author(s): Yuji Itoh, Kiyoshi Ikeda, Takashi Suzuki, and Hiroaki Tokiwa
  • Organizer: 21st International Symposium on Glycoconjuagates(Glyco21)
  • Place of Presentation: Vienna, Austria
  • Year and Date: 20110821-26
• [Presentation] All-Electronic Calculations(AEC)-Docking Procedure Based on the FMO-ONIOM Method (2011)
  • Author(s): Sayaka Motoyoshi, Takeshi Ishikawa, Kazuo Kuwata, and Hiroaki Tokiwa
  • Organizer: Ninth Triennial Congress of the WORLD ASSOCIATION OF THEORETICAL AND COMPUTATIONAL CHEMISTS(WATOC 2011)
  • Place of Presentation: Sanctiago de Compostela, Spain
  • Year and Date: 20110717-22
• [Presentation] Theoretical study of regioselectivities in the Diels-Alder reaction between substituted benzynes and furans (2011)
  • Author(s): Akira Takagi, Takashi Ikawa, Yuji Itoh, Hiroaki Tokiwa, Shuji Akai
  • Organizer: Ninth Triennial Congress of the WORLD ASSOCIATION OF THEORETICAL AND COMPUTATIONAL CHEMISTS(WATOC 2011)
  • Place of Presentation: Sanctiago de Compostela, Spain
  • Year and Date: 20110717-22
• [Presentation] Ab Initio Fragment Molecular Orbital Study of Peroxisome Proliferator-Activated Receptor(PPAR) Pan Agonist (2011)
  • Author(s): Norika Hanada, Hiroyuki Miyachi, and Hiroaki Tokiwa
  • Organizer: Ninth Triennial Congress of the WORLD ASSOCIATION OF THEORETICAL AND COMPUTATIONAL CHEMISTS(WATOC 2011)
  • Place of Presentation: Sanctiago de Compostela, Spain
  • Year and Date: 20110717-22
• [Presentation] ビタミンD受容体パーシャルアゴニストの設計・合成および生物活性の検討 (2011)
  • Author(s): 工藤健, 石澤通康, 宇野茂之, 常盤広明, 槇島誠, 山田幸子
  • Organizer: 第22回レチノイド研究会学術集会
  • Place of Presentation: 東京
  • Year and Date: 2011-11-11
• [Presentation] ケイ素及びホウ素置換ベンザインの環化付加反応における位置選択性発現機構の計算化学的解析 (2011)
  • Author(s): 高木晃, 井川貴詞, 後藤雅彦, 青山祐也, 赤井周司, 伊東祐仁, 常盤広明
  • Organizer: 第37回反応と合成のシンポジウム
  • Place of Presentation: 徳島
  • Year and Date: 2011-11-08
• [Presentation] 最新の理論化学計算はどのように生体触媒反応解析に役立つのか (2011)
  • Author(s): 常盤広明
  • Organizer: 第14回生体触媒化学シンポジウム
  • Place of Presentation: 静岡
  • Year and Date: 2011-09-24
• [Presentation] 予防を目指した天然物質および機能性食品のメカニズム解明:最新の受容体研究を基盤として (2011)
  • Author(s): 常盤広明
  • Organizer: 応用薬理シンポジウム
  • Place of Presentation: 千葉
  • Year and Date: 2011-09-03
• [Presentation] 嵩高い置換基を有するPPARγアゴニストは何故高活性を示すか (2011)
  • Author(s): 花田典佳, 山岸賢司, 宮地弘幸, 常盤広明
  • Organizer: 創薬懇話会2011 in Okayama
  • Place of Presentation: 岡山
  • Year and Date: 2011-07-06
• [Presentation] ベンザインの位置選択的[3+2]環化付加反応:多置換ヘテロ芳香族化合物の位置制御合成 (2011)
  • Author(s): 井川貴詞、高木晃、後藤雅彦、青山祐也、西山剛、伊東祐仁、常盤広明、赤井周司
  • Organizer: 第9回次世代を担う有機化学シンポジウム
  • Place of Presentation: 東京
  • Year and Date: 2011-05-28
• [Presentation] 新世紀の創薬を支える"日本発"のサイエンス (2011)
  • Author(s): 常盤広明
  • Organizer: 日本薬学会第131年会
  • Place of Presentation: 静岡
  • Year and Date: 2011-03-30
• [Presentation] Ab initio Fragment Molecular Orbital Study on novel anti-parainfluenza drugs (2010)
  • Author(s): Yuji Itoh, Kenji Yamagishi, Kiyoshi Ikeda, Takashi Suzuki, and Hiroaki Tokiwa
  • Organizer: The International Chemical Congress of Pacific Basin Societies(PACIFICHEM2010)
  • Place of Presentation: Honolulu, Hawai, U. S. A
  • Year and Date: 20101215-20
• [Presentation] Theoretical Study of Agonist Ligands of the Vitamin D Receptor (2010)
  • Author(s): Sayaka Motoyoshi, Kenji Yamagishi, Sachiko Yamada, Hiroaki Tokiwa
  • Organizer: The International Chemical Congress of Pacific Basin Societies(PACIFICHEM2010)
  • Place of Presentation: Honolulu, Hawai, U. S. A
  • Year and Date: 20101215-20
• [Presentation] Ab initio quantum chemical interaction analysis between influenza neuraminidase and anti-influenza drugs using novel computer-assisted procedure (2010)
  • Author(s): Miho Sakai, Kenji Yamagishi, Yasuo Suzuki, Hiroaki Tokiwa
  • Organizer: The International Chemical Congress of Pacific Basin Societies(PACIFICHEM2010)
  • Place of Presentation: Honolulu, Hawai, U. S. A
  • Year and Date: 20101215-20
• [Presentation] Ab initio fragment orbital study of interaction analysis between influenza neuraminidase and anti-influenza drugs (2010)
  • Author(s): Hiroaki Tokiwa
  • Organizer: Gordon Research Conferences "Computational Chemistry"
  • Place of Presentation: Les Diablerets, Swiss
  • Year and Date: 20100829-0903
• [Presentation] Theoretical interaction analysis between influenza neuraminidase and anti-influenza drugs using Fragment MO method (2010)
  • Author(s): Kenji Yamagishi, Miho Sakai, Yasuo Suzuki, Hiroaki Tokiwa
  • Organizer: The 25th International Carbonhydorate Symposium(ICS2010)
  • Place of Presentation: Makuhari, Japan
  • Year and Date: 20100801-06
• [Presentation] 部分構造最適化法を利用したab initioドッキング法の開発4 (2010)
  • Author(s): 元吉沙也加, 山岸賢司, 山田幸子, 常盤広明
  • Organizer: 第29回メディシナルケミストリーシンポジウム
  • Place of Presentation: 京都
  • Year and Date: 2010-11-18
• [Presentation] Iフラグメント分子軌道法を用いた抗インフルエンザ薬とNAとの理論的相互作用解析 (2010)
  • Author(s): 酒井美帆, 山岸賢司, 鈴木康夫, 常盤広明
  • Organizer: 第29回メディシナルケミストリーシンポジウム
  • Place of Presentation: 京都
  • Year and Date: 2010-11-18
• [Presentation] ヒトパラインフルエンザウイルス(hPIV)感染症の新規治療薬の理論的分子設計 (2010)
  • Author(s): 伊東祐仁, 山岸賢司, 池田潔, 鈴木隆, 常盤広明
  • Organizer: 第29回メディシナルケミストリーシンポジウム
  • Place of Presentation: 京都
  • Year and Date: 2010-11-18
• [Presentation] FMO-ONIOM法を用いたab initioドッキング法の開発と応用 (2010)
  • Author(s): 元吉沙也加, 山岸賢司, 山田幸子, 常盤広明
  • Organizer: 第54回日本薬学会関東支部大会
  • Place of Presentation: 八王子,東京
  • Year and Date: 2010-10-02
• [Presentation] ヒトパラインフルエンザウイルス(hPIV)感染症の新規治療薬の理論的分子設計 (2010)
  • Author(s): 伊東祐仁, 山岸賢司, 池田潔, 鈴木隆, 常盤広明
  • Organizer: 第54回日本薬学会関東支部大会
  • Place of Presentation: 八王子,東京
  • Year and Date: 2010-10-02
• [Presentation] フラグメント分子軌道法を用いた抗インフルエンザ薬とNAとの理論的相互作用解析 (2010)
  • Author(s): 酒井美帆, 山岸賢司, 鈴木康夫, 常盤広明
  • Organizer: 第54回日本薬学会関東支部大会
  • Place of Presentation: 八王子,東京
  • Year and Date: 2010-10-02
• [Presentation] ヒトパラインフルエンザウイルス(hPIV)感染症の新規治療薬の理論的分子設計 (2010)
  • Author(s): 伊東祐仁, 山岸賢司, 池田潔, 鈴木隆, 常盤広明
  • Organizer: 日本プロセス化学会2010サマーシンポジウム
  • Place of Presentation: 江戸川,東京
  • Year and Date: 2010-07-15
• [Presentation] ハイスループット創薬を志向したIT分子設計の"ニュートレンド" (2010)
  • Author(s): 常盤広明
  • Organizer: 第9回国際バイオEXPO
  • Place of Presentation: 東京
  • Year and Date: 2010-07-02
• [Presentation] PPAR-リガンド複合体に関する理論的研究 (2010)
  • Author(s): 宗像紫織, 元吉沙也加, 山岸賢司, 山田幸子, 青木康展, 白石寛明, 常盤広明
  • Organizer: 第37回日本トキシコロジー学会学術年会
  • Place of Presentation: 宜野湾,沖縄
  • Year and Date: 2010-06-18
• [Presentation] リガンドを介した1α, 25(OH) 2D3/VDRのアロステリックコミュニケーション (2010)
  • Author(s): 元吉沙也加, 山岸賢司, 槇島誠, 山田幸子, 常盤広明
  • Organizer: 第62回日本ビタミン学会
  • Place of Presentation: 盛岡
  • Year and Date: 2010-06-12
• [Presentation] FMO法を用いた抗インフルエンザ薬とNAとの理論的相互作用解析 (2010)
  • Author(s): 酒井美帆, 山岸賢司, 鈴木康夫, 常盤広明
  • Organizer: 日本分子生物学会第10回春季シンポジウム
  • Place of Presentation: 松島,宮城
  • Year and Date: 2010-06-07
• [Presentation] In Silico Molecular Screening of Novel Vitamin D Ligands (2009)
  • Author(s): Kenji Yamagishi, Sachiko Yamada, Makoto Makishima, Hiroaki Tokiwa
  • Organizer: 14th Workshop on Vitamin D
  • Place of Presentation: Brugge, Belgium
  • Year and Date: 20091004-08
• [Presentation] X-RAY Crystal Structure, Biological Activity and Structure-Activity Relationship of Novel Vitamin D Partial Agonist/Antagonist (2009)
  • Author(s): Sachiko Yamada, Makoto Nakabayashi, Teikichi Ikura, Nobutoshi Ito, Nobuko Yoshimoto, Masato Shimizu, Kenji Yamagishi, Takeru Kudo, Hiroaki Tokiwa, Mihwa Chuma, Makoto Makishima
  • Organizer: 14th Workshop on Vitamin D
  • Place of Presentation: Brugge, Belgium
  • Year and Date: 20091004-08
• [Presentation] Application of ab initio docking procedure based on FMO-ONIOM method to novel VDR ligands (2009)
  • Author(s): Sayaka Motoyoshi, Kenji Yamagishi, Sachiko Yamada, Makoto Makishima, Hiroaki Tokiwa
  • Organizer: 14th Workshop on Vitamin D
  • Place of Presentation: Brugge, Belgium
  • Year and Date: 20091004-08
• [Presentation] Development and Application of ab initio Docking Procedure Based on the FMO-ONIOM Method (2009)
  • Author(s): Sayaka Motoyoshi, Kenji Yamagishi, Sachiko Yamada, Hiroaki Tokiwa
  • Organizer: CREST International, Symposium on Theory And Simulations of Complex Molecular Systems
  • Place of Presentation: Kyoto, Japan
  • Year and Date: 20090719-21
• [Book] How Does FMO Method Help in Studying Viruses and Their Binding to Receptors?", in『The Fragment Molecular Orbital Method : Practical Applications to Large Molecular Systems』 (2009)
  • Author(s): T. Sawada, T. Hashimoto, H. Tokiwa, T. Suzuki, H. Nakano, H. Ishida, M. Kiso, Y. Suzuki
  • Total Pages: 193-216
  • Publisher: CRC Press
• [Remarks]
  • URL: http://www2.rikkyo.ac.jp/web/tokiwa
• [Patent(Industrial Property Rights)] パーシャルアゴニスト活性を持つ新規ビタミンD受容体モジュレーター (2012)
  • Inventor(s): 槇島誠,山田幸子, Antonio Mourino,常盤広明,工藤健,渡會友祐,前川和樹
  • Industrial Property Rights Holder: 槇島誠,山田幸子, Antonio Mourino,常盤広明,工藤健,渡會友祐,前川和樹
  • Industrial Property Number: PCT/JP2012/05525
  • Filing Date: 2012-03-01
  • Overseas
• [Patent(Industrial Property Rights)] パーシャルアゴニスト活性を持つ新規ビタミンD受容体モジュレーター (2011)
  • Inventor(s): 山田幸子、槇島誠、常盤広明、工藤健
  • Industrial Property Rights Holder: 山田幸子、槇島誠、常盤広明、工藤健
  • Industrial Property Number: 特許2011-045022
  • Filing Date: 2011-03-02