Elucidation of physiological role of the fatty acid receptor bycomputer simulation and the fluorescent probe detection system

• Project/Area Number: 23659038
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Biological pharmacy
• Research Institution: Kyoto University
• Principal Investigator: HIRASAWA Akira 京都大学, 大学院・薬学研究科, 准教授 (70242633)
• Co-Investigator(Renkei-kenkyūsha): LIU Ning 京都大学, 大学院・薬学研究科, 研究員 (70464196) ; IIDA Keiko 京都大学, 大学院・薬学研究科, 教務補佐 (00422999) ; AWAJI Takeo 埼玉医科大学, 医学部, 講師 (60297546)
• Project Period (FY): 2011 – 2012
• Project Status: Completed (Fiscal Year 2012)
• Budget Amount: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000); Fiscal Year 2012: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2011: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 分子生物学脂肪酸受容体 / GPR40 / GPR120 / 蛍光プローブ / 肥満 / シミュレーション / 脂肪酸受容体 / ドッキングシミュレーション

Research Abstract

The free fatty acid GPR40 receptor and GPR120 are GPCRs whose endogenous ligands are medium- and long-chain FFAs, and they are important in regulating insulin and GLP-1 secretion respectively.T o clarify the mechanism of diet-induced obesity caused by GPR120 defect, we performed physiological, expression profile and lipidomics analysis and developed a mathematical model. We succeeded to find the compound with the highest predicted selectivity for GPR40 receptors from this structure-activity relationship analysis.Furthermore, we analyzed in more detail physiology GPR120 with a fluorescentprobe in order to detect a direct interaction of the receptor. We revealed that the lipid sensor GPR120 is involved in obesity in both mice and humans.A large contribution to drug development using this study results is expected

Research Products

• [Journal Article] Diversity-oriented synthesis of pyrazolo[4,3-b]indoles by gold-catalysed three-component annulation: application to the development of a new class of CK2 inhibitors (2013)
  • Author(s): Hou Z, Oishi S, Suzuki Y, Kure T, Nakanishi I, Hirasawa A, Tsujimoto G, Ohno H, Fujii N
  • Journal Title: Org Biomol Chem Volume: 11 Pages: 3288-3296
  • NAID: 120005474525
  • Peer Reviewed
• [Journal Article] FFA1-selective agonistic activity based on docking simulation using FFA1 and GPR120 homology models (2013)
  • Author(s): Takeuchi M, Hirasawa A, Hara T, Kimura I, Hirano T, Suzuki T, Miyata N, Awaji T, Ishiguro M, Tsujimoto G
  • Journal Title: Br J Pharmacol Volume: 168 Pages: 1570-1583
  • Peer Reviewed
• [Journal Article] FFA1-selective agonistic 1570..1583 activity based on docking simulation using FFA1 and GPR120 homology models (2013)
  • Author(s): Masato Takeuchi
  • Journal Title: British Journal of Pharmacology Volume: 168 Issue: 7 Pages: 1570-1583
  • DOI: 10.1111/j.1476-5381.2012.02052.x
  • Peer Reviewed
• [Journal Article] Diversity-oriented synthesis of pyrazolo[4,3-b]indoles by gold-catalysed three-component annulation: application to the development of a new class of CK2 inhibitors (2013)
  • Author(s): Hou Z, Oishi S, Suzuki Y, Kure T, Nakanishi I., Hirasawa A, Tsujimoto G, Ohno H, Fujii N.
  • Journal Title: Org. Biomol. Chem. Volume: 11 Issue: 20 Pages: 3288-3296
  • DOI: 10.1039/c3ob40223a
  • NAID: 120005474525
  • Peer Reviewed
• [Journal Article] Physiological functions of fatty acid receptors and their therapeutic potential (2012)
  • Author(s): Hara T, Hirasawa A, Ichimura A, Kimura I, Tsujimoto G.
  • Journal Title: Nihon Yakurigaku Zasshi Volume: 140 Pages: 275-279
  • NAID: 10031130803
  • Peer Reviewed
• [Journal Article] Structure-Based Design of Novel Potent Protein Kinase CK2 (CK2) Inhibitors with Phenyl-azole Scaffolds (2012)
  • Author(s): Hou Z, Nakanishi I, Kinoshita T, Takei Y, Yasue M, Misu R, Suzuki Y, Nakamura S, Kure T, Ohno H, Murata K, Kitaura K, Hirasawa A, Tsujimoto G, Oishi S, Fujii N
  • Journal Title: J Med Chem Volume: 55 Pages: 2899-2903
  • Peer Reviewed
• [Journal Article] Short-chain fatty acid receptor GPR41-mediated activation of sympathetic neurons involves synapsin 2b phosphorylation (2012)
  • Author(s): Inoue D, Kimura I, Wakabayashi M, Tsumoto H, Ozawa K, Hara T, Takei Y, Hirasawa A, Ishihama Y, Tsujimoto G
  • Journal Title: FEBS Lett Volume: 586 Pages: 1547-1554
  • Peer Reviewed
• [Journal Article] Development and application of fluorescent SDF-1 derivatives (2012)
  • Author(s): Masuda R, Oishi S, Tanahara N, Ohno H, Hirasawa A, Tsujimoto G, Kodama E, Matsuoka M, Fujii N
  • Journal Title: Future Med Chem. Volume: 4 Pages: 837-844
  • NAID: 120005285488
  • Peer Reviewed
• [Journal Article] Paradoxical Downregulation of CXC Chemokine Receptor 4 Induced by Polyphemusin II-derived Antagonists. (2012)
  • Author(s): Masuda R, Oishi S, Tanahara N, Ohno H, Hirasawa A, Tsujimoto G, Yano Y, Matsuzaki K, Navenot J M, Peiper S C, Fujii N
  • Journal Title: Bioconjug Chem
  • Peer Reviewed
• [Journal Article] Design and synthesis of a novel class of CK2 inhibitors: application of copper- and gold-catalysed cascade reactions for fused nitrogen heterocycles. (2012)
  • Author(s): Suzuki Y, Oishi S, Takei Y, Yasue M, Misu R, Naoe S, Hou Z, Kure T, Nakanishi I, Ohno H, Hirasawa A, Tsujimoto G, Fujii N
  • Journal Title: Org Biomol Chem Volume: 10 Pages: 4907-4915
  • NAID: 120005244966
  • Peer Reviewed
• [Journal Article] Paradoxical downregulation of CXC chemokine receptor 4 induced by polyphemusin II-derived antagonists. (2012)
  • Author(s): Masuda R, Oishi S, Tanahara N, Ohno H, Hirasawa A, Tsujimoto G, Yano Y, Matsuzaki K, Navenot J, Peiper S, Fujii N.
  • Journal Title: Bioconjug. Chem. Volume: 23 Issue: 6 Pages: 1259-1265
  • DOI: 10.1021/bc300084h
  • Peer Reviewed
• [Journal Article] Design and synthesis of novel class of CK2 inhibitors : application of copper- and gold-catalysed cascade reactions for fused nitrogen heterocycles. (2012)
  • Author(s): Suzuki Y, Oishi S, Takei Y, Yasue M, Misu R, Naoe S, Hou Z, Kure T, Nakanishi I, Ohno H, Hirasawa A, Tsujimoto G, Fujii N.
  • Journal Title: Org. Biomol. Chem. Volume: 10 Issue: 25 Pages: 4907-4915
  • DOI: 10.1039/c2ob25298h
  • Peer Reviewed
• [Journal Article] Development and application of fluorescent SDF-1 derivatives (2012)
  • Author(s): Masuda R, Oishi S, Tanahara N, Ohno H, Hirasawa A, Tsujimoto G, Kodama E, Matsuoka M, Fujii N.
  • Journal Title: Future Med. Chem. Volume: 4 Issue: 7 Pages: 837-844
  • DOI: 10.4155/fmc.12.31
  • NAID: 120005285488
  • Peer Reviewed
• [Journal Article] Short-chain fatty acid receptor GPR41-mediated activation of sympathetic neurons involves synapsin 2b phosphorylation (2012)
  • Author(s): Daisuke Inoue
  • Journal Title: FEBS Letters Volume: 586 Issue: 10 Pages: 1547-54
  • DOI: 10.1016/j.febslet.2012.04.021
  • Peer Reviewed
• [Journal Article] 脂肪酸受容体の生理機能と創薬標的としての可能性 (2012)
  • Author(s): 原 貴史
  • Journal Title: 日本薬理学雑誌 Volume: 140 Pages: 275-279
• [Journal Article] Structure-based Design of Novel Potent CK2 Inhibitors with Phenyl-azole Scaffolds. (2012)
  • Author(s): Z. Hou, I. Nakanishi, T. Kinoshita, Y. Takei, M. Yasue, R. Misu, Y. Suzuki, S. Nakamura, T. Kure, H. Ohno, K. Murata, K. Kitaura, A. Hirasawa, G. Tsujimoto, S. Oishi, N. Fujii.
  • Journal Title: J. Med. Chem. Volume: 55 Issue: 6 Pages: 2899-2903
  • DOI: 10.1021/jm2015167
  • Peer Reviewed
• [Journal Article] Dysfunction of lipid sensor GPR120 leads to obesity in both mouse and human (2012)
  • Author(s): Ichimura A
  • Journal Title: Nature Volume: 483 Issue: 7389 Pages: 350-354
  • DOI: 10.1038/nature10798
  • Peer Reviewed
• [Presentation] 脂肪酸センサーGPR120 は食事性肥満の原因遺伝子である (2012)
  • Author(s): 平澤明
  • Organizer: 第85回日本生化学会大会
  • Place of Presentation: 福岡県福岡国際会議場・マリンメッセ福岡
  • Year and Date: 2012-12-15
• [Presentation] 長鎖脂肪酸受容体 GPR120 の生理機能の解明と創薬応用 (2012)
  • Author(s): 平澤明
  • Organizer: 第85回日本内分泌学会学術総会招待講演
  • Place of Presentation: 愛知県名古屋国際会議場
  • Year and Date: 2012-04-19
• [Presentation] 脂肪酸センサーGPR120は食事性肥満の原因遺伝子である (2012)
  • Author(s): 平澤明
  • Organizer: 第85回日本生化学会大会
  • Place of Presentation: 福岡国際会議場・マリンメッセ福岡 (福岡県)
• [Presentation] 長鎖脂肪酸受容体GPR120の生理機能の解明と創薬応用 (2012)
  • Author(s): 平澤明
  • Organizer: 第85回日本内分泌学会学術総会
  • Place of Presentation: 名古屋国際会議場 (愛知県)
  • Invited
• [Presentation] 脂肪酸受容体GPR120の構造活性相関と薬理学的機能解析 (2012)
  • Author(s): 原貴史、平澤明、竹内理人、鮎川久美子、白井遼平、辻本豪三
  • Organizer: 第41回日本心脈管作動物質学会
  • Place of Presentation: 秋田キャッスルホテル（秋田県）
• [Presentation] 薬物スクリーニングへのイメージング技術の応用 (2012)
  • Author(s): 平澤明、辻本豪三、原貴史 シンポジウム
  • Organizer: 日本薬学会第132年会
  • Place of Presentation: 北海道大学キャンパス内（北海道）
• [Presentation] ドッキングシミュレーションに基づくGPR40アゴニストの構造活性相関 (2012)
  • Author(s): Masato Takeuchi, Akira Hirasawa, Takafumi Hara, Tatsuya Hirano, Takayoshi Suzuki, Naoki Miyata, Masaji Ishiguro and Gozoh Tsujimoto
  • Organizer: 日本薬学会第132年会
  • Place of Presentation: 北海道大学キャンパス内（北海道）
• [Presentation] Structure-Activity Relationships of GPR120 Agonists Based on a Docking Simulation (2011)
  • Author(s): 平澤明
  • Organizer: AIMECS11;Frontier of Medicinal Science
  • Place of Presentation: 京王プラザホテル（東京都）